Protease inhibitors

ABSTRACT

This invention relates to treating an infection with a virus using protease inhibitors. Examples of the protease inhibitors include compounds of formula (I). Each variable is defined in the specification

CROSS REFERENCE TO RELATED APPLICATION

Pursuant to 35 U.S.C. § 119(e), this application claims priority to U.S.Provisional Application Ser. No. 60/533,779, filed Dec. 31, 2003.

BACKGROUND

Coronavirus is a family of viruses that have the appearance of a coronawhen viewed under a microscope. Members of the coronavirus family cancause hepatitis in mice, gastroenteritis in pigs, and respiratoryinfections in birds and humans. Coronavirus was first isolated fromchickens in 1937 by Beaudette and Hudson. In 1965, Tyrrell and Bynoeused cultures of human ciliated embryonic trachea to propagate the firsthuman coronavirus in vitro.

Among the more than 30 strains of coronavirus isolated so far, three orfour infect humans. For example, the severe acute respiratory syndrome,a newly emerged infectious disease, is associated with a novelcoronavirus (Ksiazek et al., New England Journal Medicine, 2003,348(20): 1953-1966). This life-threatening respiratory disease causedworldwide outbreaks in 2003. Vaccines and drugs against severe acuterespiratory syndrome virus are being vigorously sought. Nevertheless,the progress is rather slow due to safety concerns. Thus, there exists aneed to develop drugs that are effective in treating infections withcoronaviruses, as well as infections with other viruses.

SUMMARY

This invention is based on the unexpected discovery that certainpeptide-like compounds are effective in treating viral infections byinhibiting viral proteases (e.g., coronaviral 3CL proteases,picornaviral proteases, or hepatitis C viral proteases).

In one aspect, this invention features a method for treating aninfection with a virus. The method includes administering to a subjectin need thereof an effective amount of a compound of formula (I):

In this formula, X is N(R_(a1)), O, or CH₂; or X and one of R₂ and R₃,together with the atom or atoms to which they are bonded, are C₃-C₂₀heterocycloalkyl; in which R_(a1) is H or C₁-C₁₅ alkyl; R₁ is H, C₁-C₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl,C(O)R_(b1), CO₂R_(b1), C(O)NR_(b1)R_(b2), C(O)—N(R_(b1))—OR_(b2),C(S)R_(b1), C(S)NR_(b1)R_(b2), S(O)R_(b1), SO₂R_(b1), S(O)NR_(b1)R_(b2),S(O)—N(R_(b1))—OR_(b2), SO₂NR_(b1)R_(b2), or SO₃R_(b1); in which each ofR_(b1) and R_(b2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; each of R₂ and R₃,independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, aryl, OR_(c1), SR_(c1), or NR_(c1)R_(c2);or X and one of R₂ and R₃, together with the atom or atoms to which theyare bonded, are C₃-C₂₀ heterocycloalkyl; in which each of R_(c1) andR_(c2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; each of R₄ and R₅, independently,is H, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; one of R₆ and R₇ is C₁-C₁₅ alkyl substituted withC₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; and the other of R₆ and R₇is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; R₈ is H, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, OR_(d1), or SR_(d1); in whichR_(d1) is H and C₁-C₁₅ alkyl; and each of R₉ and R₁₀, independently, isH, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, aryl, C(O)R_(e1), CO₂R_(e1), C(O)NR_(e1)R_(e2),C(O)—N(R_(e1))—OR_(e2), C(S)R_(e1), C(S)NR_(e1)R_(e2), CN, NO₂,S(O)R_(e1), SO₂R_(e1), S(O)NR_(e1)R_(e2), S(O)—N(R_(e1))—OR_(e2),SO₂NR_(e1)R_(e2), SO₃R_(e1), PO(OR_(e1))(OR_(e2)), PO(R_(e1))(R_(e2)),PO(NR_(e1)R_(e2))(OR_(e3)), PO(NR_(e1)R_(e2))(NR_(e3)R_(e4)),C(O)—N(R_(e1))—NR_(e2)R_(e3), or C(S)—N(R_(e1))—NR_(e2)R_(e3); or R₈ andR₁₀, taken together, is C₃-C₂₀ cycloalkyl or C₃-C₂₀ heterocycloalkyl; orR₉ and R₁₀, taken together, is C₃-C₂₀ cycloalkyl or C₃-C₂₀heterocycloalkyl; in which each of R_(e1), R_(e2), R_(e3), and R_(e4),independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; or any two of R_(e1), R_(e2),R_(e3), and R_(e4), together with the atom or atoms to which they arebonded, is C₃-C₂₀ heterocycloalkyl; and the virus is a coronavirus or ahepatitis C virus.

In particular, this invention features a method for treating aninfection with a severe acute respiratory syndrome virus, a humancoronavirus 229E, or a hepatitis C virus, by administering to a subjectin need thereof an effective amount of a compound of formula (I) shownabove.

For example, one can administer to a subject infected with a virus(e.g., a severe acute respiratory syndrome virus) a compound of formula(I), in which X is N(R_(a1)) or O; or X and one of R₂ and R₃, togetherwith the atom or atoms to which they are bonded, are C₃-C₂₀heterocycloalkyl; R₁ is H, C(O)R_(b1), CO₂R_(b1), C(O)NR_(b1)R_(b2),C(S)NR_(b1)R_(b2), or SO₂R_(b1); each of R₂ and R₃, independently, is Hor C₁-C₁₅ alkyl; or X and one of R₂ and R₃, together with the atom oratoms to which they are bonded, are C₃-C₂₀ heterocycloalkyl; each of R₄and R₅, independently, is H or C₁-C₁₅ alkyl; one of R₆ and R₇ is C₁-C₁₅alkyl substituted with C₃-C₂₀ heterocycloalkyl, and the other of R₆ andR₇ is H; R₈ is H; and each of R₉ and R₁₀, independently, is H orCO₂R_(e1). In this compound, one of R₆ and R₇ can be

one of R₂ and R₃ can be H or C₁-C₁₅ alkyl optionally substituted withhalogen, heteroaryl, aryl, OR_(c1), SR_(c1), OC(O)R_(c1), CO₂R_(c1),C(O)NR_(c1)R_(c2), NR_(c1)R_(c2), N(R_(c1))—CO₂R_(c2),N(R_(c1))—C(O)R_(c2), N(R_(c1))—C(O)—NR₂R_(c3), N(R_(c1))—SO₂R_(c2),SO₂R_(c1), or O—SO₂—R_(c1); or X and one of R₂ and R₃, together with theatom or atoms to which they are bonded, are C₃-C₂₀ heterocycloalkyl; inwhich R_(c3) is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; and one of R₄ and R₅ can be H orC₁-C₁₅ alkyl optionally substituted with halogen, aryl, OR_(f1),SR_(f1), CO₂R_(f1), C(O)NR_(f1)R_(f2), SO₂R_(f1), SO₃R_(f1), orNR_(f1)R_(f2); in which each of R_(f1) and R_(f2), independently, is H,C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, oraryl.

The term “treating” refers to administering one or more compounds of theinvention to a subject, who has an infection with a virus, a symptom ofsuch an infection, or a predisposition toward such an infection, withthe purpose to confer a therapeutic effect, e.g., to cure, relieve,alter, affect, ameliorate, or prevent the infection with a virus, thesymptom of it, or the predisposition toward it. The term “an effectiveamount” refers to the amount of one or more active compounds of theinvention that is required to confer a therapeutic effect on a treatedsubject.

The term “alkyl” refers to a saturated or unsaturated, linear orbranched, non-aromatic hydrocarbon moiety, such as —CH₃, —CH₂—,—CH₂—CH═CH₂—, or branched —C₃H₇. The term “cycloalkyl” refers to asaturated or unsaturated, non-aromatic, cyclic hydrocarbon moiety, suchas cyclohexyl or cyclohexen-3-yl. The term “heterocycloalkyl” refers toa saturated or unsaturated, non-aromatic, cyclic moiety having at leastone ring heteroatom, such as 4-tetrahydropyranyl or 4-pyranyl. The term“aryl” refers to a hydrocarbon moiety having one or more aromatic rings.Examples of an aryl moiety include phenyl, phenylene, naphthyl,naphthylene, pyrenyl, anthryl, and phenanthryl. The term “heteroaryl”refers to a moiety having one or more aromatic rings that contain atleast one heteroatom. Examples of a heteroaryl moiety include furyl,furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl,pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl and indolyl.

Alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl mentionedherein include both substituted and unsubstituted moieties, unlessspecified otherwise. Examples of substituents on cycloalkyl,heterocycloalkyl, aryl, and heteroaryl include C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₁-C₁₀alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C₁-C₁₀alkylamino, C₁-C₂₀ dialkylamino, arylamino, diarylamino, hydroxyl,halogen, thio, C₁-C₁₀ alkylthio, arylthio, C₁-C₁₀ alkylsulfonyl,arylsulfonyl, cyano, nitro, acyl, acyloxy, carboxyl, and carboxylicester. On the other hand, examples of substituents on alkyl include allof the above-recited substituents except C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl,and C₂-C₁₀ alkynyl. Cycloalkyl, heterocycloalkyl, aryl, and heteroarylalso include fused groups.

In another aspect, this invention features a method for inhibiting aviral protease (e.g., a coronaviral 3CL protease or a hepatitis C viralprotease) in a cell. The method includes contacting the cell with aneffective amount of a compound of formula (I) shown above. Inparticular, this invention features a method for inhibiting a severeacute respiratory syndrome viral 3CL protease, a human coronaviral 229Eprotease, or a hepatitis C viral protease.

In still another aspect, this invention features a compound of formula(I) shown above except that R₁ is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, C(O)R_(b1), CO₂R_(b2),C(O)NR_(b3)R_(b4), C(O)—N(R_(b3))—OR_(b4), C(S)R_(b3),C(S)NR_(b3)R_(b4), S(O)R_(b3), SO₂R_(b3), S(O)NR_(b3)R_(b4),S(O)—N(R_(b3))—OR_(b4), SO₂NR_(b3)R_(b4), or SO₃R_(b3); in which R_(b1)is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,6-membered heteroaryl, fused heteroaryl, aryl, or NHCO₂R_(b5); R_(b2) isH, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, aryl, heteroaryl, orC₁-C₁₅ alkyl optionally substituted with halogen, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, OR_(b5), CO₂R_(b5), or S(O)₂R_(b5);and each of R_(b3) and R_(b4), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; R_(b5) beingH, C₁-C₁₅ alkyl, heteroaryl, or aryl.

Referring to formula (I), a subset of the just-described compounds arethose in which X is N(R_(a1)); or X and one of R₂ and R₃, together withthe atom or atoms to which they are bonded, are C₃-C₂₀ heterocycloalkyl;R₁ is H, C(O)R_(b1), CO₂R_(b2), C(O)NR_(b1)R_(b2), C(S)NR_(b1)R_(b2), orSO₂R_(b1), in which R_(b1) is H, aryl, or C₁-C₁₅ alkyl optionallysubstituted with halogen, aryl, or NHCO₂R_(b5); and R_(b2) is aryl orC₁-C₁₅ alkyl optionally substituted with halogen, OR_(b5), or CO₂R_(b5);each of R₂ and R₃, independently, is H or C₁-C₁₅ alkyl optionallysubstituted with OR_(c1), C(O)—NR_(c1)R_(c2), NR_(c1)R_(c2),N(R_(c1))—CO₂R_(c2), N(R_(c1))—SO₂R_(c2), or O—SO₂—R_(c1); or X and oneof R₂ and R₃, together with the atom or atoms to which they are bonded,are C₃-C₂₀ heterocycloalkyl; each of R₄ and R₅, independently, is H orC₁-C₁₅ alkyl; one of R₆ and R₇ is C₁-C₁₅ alkyl substituted with C₃-C₂₀heterocycloalkyl, and the other of R₆ and R₇ is H; R₈ is H; and each ofR₉ and R₁₀, independently, is H or CO₂R_(e1). In these compounds, one ofR₆ and R₇ can be

and one of R₄ and R₅ can be H or C₁-C₁₅ alkyl optionally substitutedwith aryl.

In still another aspect, this invention features a compound of formula(I) shown above except that R₁ is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, C(O)R_(b1), CO₂R_(b2),C(O)NR_(b2)R_(b3), C(O)—N(R_(b2))—OR_(b3), C(S)R_(b2),C(S)NR_(b2)R_(b3), S(O)R_(b2), SO₂R_(b2)S(O)NR_(b2)R_(b3),S(O)—N(R_(b2))—OR_(b3), SO₂NR_(b2)R_(b3), or SO₃R_(b2); in which R_(b1)is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, aryl,6-membered heteroaryl, or fused heteroaryl; and each of R_(b2) andR_(b3), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, aryl, or heteroaryl; and one of R₂ and R₃ is C₁-C₁₅alkyl substituted with halogen, OR_(c1), SR_(c1), CO₂R_(c1),OC(O)R_(c1), C(O)NR_(c1)R_(c2), SO₂R_(c1), O—SO₂—R_(c1), NR_(c1)R_(c2),N(R_(c1))—C(O)R_(c2), N(R_(c1))—CO₂R_(c2), N(R_(c1))—SO₂R_(c2),N(R_(c1))—C(O)—N(R_(c2)R_(c3)); the other of R₂ and R₃ is H, C₁-C₁₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl,OR_(c1), SR_(c1), or NR_(c1)R_(c2); in which each of R_(c1), R_(c2), andR_(c3), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl.

Referring to formula (I), a subset of the just-described compounds arethose in which X is N(R_(a1)) or O; or X and one of R₂ and R₃, togetherwith the atom or atoms to which they are bonded, are C₃-C₂₀heterocycloalkyl; R₁ is CO₂R_(b2), in which R_(b2) is alkyl substitutedwith aryl; one of R₂ and R₃ is C₁-C₁₅ alkyl substituted with OR_(c1),SR_(c1), OC(O)R_(c1), CO₂R_(c1), C(O)NR_(c1)R_(c2), SO₂R_(c1),O—SO₂—R_(c1), NR_(c1)R_(c2), N(R_(c1))—C(O)R_(c2), N(R_(c1))—CO₂R_(c2),N(R_(c1))—SO₂R_(c2), N(R_(c1))—C(O)—N(R_(c2)R_(c3)), and the other of R₂and R₃ is H; or X and one of R₂ and R₃, together with the atom or atomsto which they are bonded, are C₃-C₂₀ heterocycloalkyl; each of R₄ andR₅, independently, is H or C₁-C₁₅ alkyl; one of R₆ and R₇ is C₁-C₁₅alkyl substituted with C₃-C₂₀ heterocycloalkyl, and the other of R₆ andR₇ is H; R₈ is H; and each of R₉ and R₁₀, independently, is H, CN,C(O)R_(e1), CO₂R_(e1), or C(O)NR_(e1)R_(e2); or R₉ and R₁₀, takentogether, are C₃-C₂₀ heterocycloalkyl. In these compounds, one of R₆ andR₇ can be

and one of R₄ and R₅ can be H or C₁-C₁₅ alkyl optionally substitutedwith aryl, C₃-C₂₀ cycloalkyl, OR_(f1), SR_(f1), NR_(f1)R_(f2), orC(O)NR_(f1)R_(f2); in which each of R_(f1) and R_(f2), independently, isH, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl,or aryl.

In still another aspect, this invention features a compound of formula(I) shown above except that R₁ is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, C(O)R_(b1), CO₂R_(b2),C(O)NR_(b2)R_(b3), C(O)—N(R_(b2))—OR_(b3), C(S)R_(b2),C(S)NR_(b2)R_(b3), S(O)R_(b2), SO₂R_(b2), S(O)NR_(b2)R_(b3),S(O)—N(R_(b2))—OR_(b3), SO₂, NR_(b2), R_(b3), or SO₃R_(b2); in whichR_(b1) is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,aryl, 6-membered heteroaryl, or fused heteroaryl; and each of R_(b2) andR_(b3), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, aryl, or heteroaryl; one of R₄ and R₅ is C₁-C₁₅ alkylsubstituted with halogen, OR_(d1), SR_(d1), CO₂R_(d1), C(O)NR_(d1)R₂,SO₂R_(d1), SO₃R_(d1), or NR_(d1)R_(d2); the other of R₄ and R₅ is H,halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; in which each of R_(d1) and R_(d2), independently,is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; R₈ is H, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, OR_(e1), or SR_(e1); in whichR_(e1) is H and C₁-C₁₅ alkyl; and each of R₉ and R₁₀, independently, isH, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, aryl, C(O)R_(f1), CO₂R_(f1), C(O)NR_(f1)R_(f2),C(O)—N(R_(f1))—OR_(f2), C(S)R_(f1), C(S)NR_(f1)R_(f2), CN, NO₂,S(O)R_(f1), SO₂R_(f1), S(O)NR_(f1)R_(f2), S(O)—N(R_(f1))—OR_(f2),SO₂NR_(f1)R_(f2), SO₃R_(f1), PO(OR_(f1))(OR_(f2)), PO(R_(f1))(R_(f2)),PO(NR_(f1)R_(f2))(OR_(f3)), PO(NR_(f1)R_(f2))(NR_(f3)R_(f4)),C(O)—N(R_(f1))—NR_(f2)R_(f3), or C(S)—N(R_(f1))—NR_(f2)R_(f3); or R₈ andR₁₀, taken together, is C₃-C₂₀ cycloalkyl or C₃-C₂₀ heterocycloalkyl; orR₉ and R₁₀, taken together, is C₃-C₂₀ cycloalkyl or C₃-C₂₀heterocycloalkyl; in which each of R_(f1), R_(f2), R_(f3), and R_(f4),independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; or any two of R_(f1), R_(f2),R_(f3), and R_(f4), together with the atom or atoms to which they arebonded, is C₃-C₂₀ heterocycloalkyl.

Referring to formula (I), a subset of the just-described compounds arethose in which X is N(R_(a1)) or O; R₁ is CO₂R_(b2), in which R_(b2) isalkyl substituted with aryl; each of R₂ and R₃, independently, is H orC₁-C₁₅ alkyl optionally substituted with aryl; one of R₄ and R₅ isC₁-C₁₅ alkyl substituted with SR_(d1) or C(O)NR_(d2)R_(d2), and theother of R₄ and R₅ is H; one of R₆ and R₇ is C₁-C₁₅ alkyl substitutedwith C₃-C₂₀ heterocycloalkyl, and the other of R₆ and R₇ is H; R₈ is H;and each of R₉ and R₁₀, independently, is H or CO₂R_(f1). In thesecompounds, one of R₆ and R₇ can be

In a further aspect, this invention features a method for treating aninfection with a virus. The method includes administering to a subjectin need thereof an effective amount of a compound of formula (II):

In this formula, X is N(R_(a1)), O, or CH₂; or X and one of R₂ and R₃,together with the atom or atoms to which they are bonded, are C₃-C₂₀heterocycloalkyl; in which R_(a1) is H or C₁-C₁₅ alkyl; R₁ is H, C₁-C₁₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl,C(O)R_(b1), CO₂R_(b1), C(O)NR_(b1)R_(b2), C(O)—N(R_(b1))—OR_(b2),C(S)R_(b1), C(S)NR_(b1)R_(b2), S(O)R_(b1), SO₂R_(b1), S(O)NR_(b1)R_(b2),S(O)—N(R_(b1))—OR_(b2), SO₂NR_(b1)R_(b2), or SO₃R_(b1); in which each ofR_(b1) and R_(b2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; each of R₂ and R₃,independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, aryl, OR_(c1), SR_(c1), or NR_(c1)R_(c2);or X and one of R₂ and R₃, together with the atom or atoms to which theyare bonded, are C₃-C₂₀ heterocycloalkyl; in which each of R_(c1) andR_(c2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; each of R₄ and R₅, independently,is H, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; and one of R₆, R₇, and R₈ is C₁-C₁₅ alkylsubstituted with C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; and theothers of R₆, R₇, and R₈, independently, is H, halogen, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, OR_(d1),SR_(d1), C(O)R_(d1), CO₂R_(d1), C(O)NR_(d1)R_(d2), orC(O)—N(R_(d1))—OR_(d2); in which R_(d1) and R_(d2), independently, is H,C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, oraryl; and the virus is a coronavirus or a hepatitis C virus.

In particular, this invention features a method for treating aninfection with a severe acute respiratory syndrome virus, a humancoronavirus 229E, or a hepatitis C virus, by administering to a subjectin need thereof an effective amount of a compound of formula (II) shownabove.

For example, one can administer to a subject infected with a virus(e.g., a severe acute respiratory syndrome virus) a compound of formula(II), in which X is N(R_(a1)) or O; R₁ is CO₂R_(b1), in which R_(b1) isalkyl substituted with aryl; each of R₂ and R₃, independently, is H orC₁-C₁₅ alkyl optionally substituted with aryl, OR_(c1), CO₂R_(c1),N(R_(c1))—C(O)R_(c2), or OC(O)—NR_(c1)R_(c2); each of R₄ and R₅,independently, is H or C₁-C₁₅ alkyl; R₆ is C₁-C₁₅ alkyl substituted withC₃-C₂₀ heterocycloalkyl; R₇ is H; and R₈ is C(O)R_(d1), CO₂R_(d1),C(O)NR_(d1)R_(d2), or C₁-C₁₅ alkyl optionally substituted with halogenor OH. In these compounds, one of R₆ and R₇ can be

In a further aspect, this invention features a method for inhibiting aviral protease (e.g., a coronaviral 3CL protease or a hepatitis C viralprotease) in a cell, by contacting the cell with an effective amount ofa compound of formula (II) shown above. In particular, this inventionfeatures a method for inhibiting a severe acute respiratory syndromeviral 3CL protease, a human coronaviral 229E protease, or a hepatitis Cviral protease.

In a further aspect, this invention features a compound of formula (II)shown above.

In still a further aspect, this invention features a method for treatingan infection with a picornavirus (e.g., an enterovirus or a rhinovirus).The method includes administering to a subject in need thereof aneffective amount of a compound of formula (I) or a compound of formula(II).

In still a further aspect, this invention features a method forinhibiting a picornaviral protease (e.g., an enteroviral protease or arhinoviral 3C protease) in a cell. The method includes contacting thecell with an effective amount of a compound of formula (I) or a compoundof formula (II).

In yet a further aspect, this invention features a chemical syntheticmethod. The method includes reducing a compound of formula (III):

to form an alcohol, followed by reacting the alcohol with Ph₃P═COOR inthe presence of pyridine sulfur trioxide to give a compound of formula(IV):

in which P₁ is an amino-protecting group; P₂ is a carboxyl-protectinggroup; and R is C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl. In formulas (III) and (IV), P₁can be t-butoxycarbonyl, benzyloxycarbonyl, acetyl, phenylcarbonyl, ortrialkylsilyl; P₂ can be C₁-C₁₅ alkyl; and R can be C₁-C₁₅ alkyl.

In particular, the chemical synthetic method can further includeremoving the amino-protecting group P₁ of the compound of formula (IV)to form a first de-protected intermediate, and then reacting the firstde-protected intermediate with P₃HN—CH(R₅)—COOH to give a compound offormula (V):

in which P₃ is an amino-protecting group and R₅ is H, halogen, C₁-C₁₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl.The method can further include removing the amino-protecting group P₃ ofthe compound of formula (V) to form a second de-protected intermediate,and then reacting the second de-protected intermediate withR₁HN—CH(R₂)—COOH to give a compound of formula (VI):

in which R₁ is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, aryl, C(O)R_(b1), CO₂R_(b1),C(O)NR_(b1)R_(b2), C(O)—N(R_(b1))—OR_(b2), C(S)R_(b1),C(S)NR_(b1)R_(b2), S(O)R_(b1), SO₂R_(b1), S(O)NR_(b1)R_(b2),S(O)—N(R_(b1))—OR_(b2), SO₂NR_(b1)R_(b2), or SO₃R_(b1); in which each ofR_(b1) and R_(b2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; and R₂ is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, OR_(c1),SR_(c1), or NR_(c1)R_(c2); or X and one of R₂ and R₃, together with theatom or atoms to which they are bonded, are C₃-C₂₀ heterocycloalkyl; inwhich each of R_(c1) and R_(c2), independently, is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl. Informulas (V) and (VI), P₃ can be t-butoxycarbonyl, benzyloxycarbonyl,acetyl, phenylcarbonyl, or trialkylsilyl; and R can be C₁-C₁₅ alkyl.

Alternatively, the chemical synthetic method mentioned above can furtherinclude removing the amino-protecting group P₁ of the compound offormula (IV) to form a first de-protected intermediate, and thenreacting the first de-protected intermediate with a compound of formula(VII):

to give a compound of formula (VI):

in which R₁ is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, aryl, C(O)R_(b1), CO₂R_(b1),C(O)NR_(b1)R_(b2), C(O)—N(R_(b1))—OR_(b2), C(S)R_(b1),C(S)NR_(b1)R_(b2), S(O)R_(b1), SO₂R_(b1), S(O)NR_(b1)R_(b2),S(O)—N(R_(b1))—OR_(b2), SO₂NR_(b1)R_(b2), or SO₃R_(b1); in which each ofR_(b1) and R_(b2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; R₂ is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, OR_(c1),SR_(c1), or NR_(c1)R_(c2); or X and one of R₂ and R₃, together with theatom or atoms to which they are bonded, are C₃-C₂₀ heterocycloalkyl; inwhich each of R_(c1) and R_(c2), independently, is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; and R₅is H, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl.

In addition, the chemical synthetic method can further include removingthe amino-protecting group P₁ of the compound of formula (IV) to form afirst de-protected intermediate, and then reacting the firstde-protected intermediate with a compound of formula (VIII):

in which n is 1, 2, or 3; P₄ is an amino-protecting group; and R₅ is H,halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; followed by removing the amino-protecting group P₄to give a compound of formula (IX):

The compound of formula (IX) can further react with R₁′COOH or R₁′COClto give a compound of formula (X):

in which R₁′ is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, aryl, or OR_(b1); R_(b1) being H, C₁-C₁₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl.In formulas (VIII), (IX), and (X), P₄ can be t-butoxycarbonyl,benzyloxycarbonyl, acetyl, phenylcarbonyl, or trialkylsilyl; and R canbe C₁-C₁₅ alkyl.

In addition, this invention encompasses a pharmaceutical compositionthat contains an effective amount of at least one of the above-mentionedcompounds and a pharmaceutically acceptable carrier.

The compounds of the invention include the compounds themselves, as wellas their salts, prodrugs, and solvates, if applicable. A salt, forexample, can be formed between an anion and a positively charged group(e.g., amino) on a compound of the invention. Examples of suitableanions include chloride, bromide, iodide, sulfate, nitrate, phosphate,citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, asalt can also be formed between a cation and a negatively charged group(e.g., carboxylate) on a compound of the invention. Examples of suitablecations include sodium ion, potassium ion, magnesium ion, calcium ion,and an ammonium cation such as tetramethylammonium ion. Examples ofprodrugs include esters and other pharmaceutically acceptablederivatives, which, upon administration to a subject, are capable ofproviding active compounds of the invention. A solvate refers to acomplex formed between an active compound of the invention and apharmaceutically acceptable solvent. Examples of pharmaceuticallyacceptable solvents include water, ethanol, isopropanol, ethyl acetate,acetic acid, and ethanolamine.

Also within the scope of this invention is a composition containing oneor more of the compounds described above for use in treating aninfection with a virus, and the use of such a composition for themanufacture of a medicament for the just-mentioned treatment.

The details of one or more embodiments of the invention are set forth inthe description below. Other features, objects, and advantages of theinvention will be apparent from the description and from the claims.

DETAILED DESCRIPTION

Shown below are the structures of compounds 1-145, exemplary compoundsof this invention:

The compounds described above can be prepared by methods well known to askilled person in the art. For example, Schemes I-IV shown below depicttypical synthetic routes for preparing exemplary compounds. In theseschemes, R₁, R₁′, R₂, and R₅ are as defined in the Summary sectionabove. Details of preparation of these compounds are provided inExamples 1-145.

As shown in Scheme I, L-glutamic acid can first be protected witht-butoxylcarbonyl and methyl. The protected L-glutamic acid(intermediate I) can then react with bromoacetonitrile and followed by aring closure reaction to form an amino acid derivative that containing a5-membered cyclic lactam (intermediate 3). Intermediate 3 cansubsequently be transformed to intermediate 5 that includes anadditional double bond. Intermediate 5 thus formed can sequentiallycouple with two amino acid derivatives to prepare a compound of formula(I). Reagents other than those shown in Scheme I can also be used. Forexample, intermediate 5 mentioned above can couple with an acidcontaining hydroxyl, before coupling to an amino acid to prepare acompound of formula (I) in which X is oxygen.

As shown in Scheme II, intermediate 5 can also couple with amino acidderivatives that contain a pyrrolidinone moiety to form certaincompounds of formula (IX). The compounds thus obtained can be furthermodified (e.g., by reacting with an acid or an acyl chloride) to obtaincompounds of formula (X).

As shown in Scheme III, intermediate 5 can also be hydrolyzed to form anacid, which in turn can react with O,N-dimethyl-hydroxylamine to form anamide. The amide can either sequentially couple with two amino acidderivatives or couple with a dipeptide derivative to form certaincompounds of formula (I). The compounds thus obtained can further reactwith Grignard reagents to form other compounds of formula (I).

As shown in Scheme IV, intermediate 3 mentioned above can alsosequentially couple with two amino acid derivatives (or couple with adipeptide derivative) to form certain compounds of formula (I). Thecompounds thus obtained can be further reduced to form alcohols oroxidized to form acids. The alcohols can be further halogenated to formhalides or oxidized to form aldehydes. The aldehydes can subsequentlyundergo either Wittig reactions or addition-elimination reactions toform certain compounds of formula (II). The acids just-mentioned canundergo, e.g., esterification reactions, Grignard reactions, oramidation reactions to form other compounds of formula (II).

A compound synthesized by the methods described above can be purified bya known method, such as column chromatography, high-pressure liquidchromatography, or recrystallization.

Other compounds of the invention can be prepared using other suitablestarting materials following the synthetic routes disclosed hereinand/or other synthetic methods known in the art. The methods describedabove may also additionally include steps, either before or after thesteps described specifically herein, to add or remove suitableprotecting groups in order to ultimately allow synthesis of thecompounds of the invention. In addition, various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizingapplicable compounds of the invention are known in the art and include,for example, those described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

The compounds mentioned herein may contain a non-aromatic double bondand one or more asymmetric centers. Thus, they can occur as racematesand racemic mixtures, single enantiomers, individual diastereomers,diastereomeric mixtures, and cis- or trans-isomeric forms. All suchisomeric forms are contemplated.

Also within the scope of this invention is a pharmaceutical compositioncontains an effective amount of at least one compound described aboveand a pharmaceutical acceptable carrier. Further, this invention coversa method of administering an effective amount of one or more of thecompounds of the invention to a patient having an infection with acoronavirus. Effective doses will vary, as recognized by those skilledin the art, depending on the types of diseases treated, route ofadministration, excipient usage, and the possibility of co-usage withother therapeutic treatment.

To practice the method of the present invention, a composition havingone or more compounds of the invention can be administered parenterally,orally, nasally, rectally, topically, or buccally. The term “parenteral”as used herein refers to subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional, or intracranial injection, aswell as any suitable infusion technique.

A sterile injectable composition can be a solution or suspension in anon-toxic parenterally acceptable diluent or solvent, such as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that canbe employed are mannitol, water, Ringer's solution, and isotonic sodiumchloride solution. In addition, fixed oils are conventionally employedas a solvent or suspending medium (e.g., synthetic mono- ordiglycerides). Fatty acid, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions can also contain a long chain alcohol diluent or dispersant,carboxymethyl cellulose, or similar dispersing agents. Other commonlyused surfactants such as Tweens or Spans or other similar emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms can also be used for the purpose of formulation.

A composition for oral administration can be any orally acceptabledosage form including capsules, tablets, emulsions and aqueoussuspensions, dispersions, and solutions. In the case of tablets,commonly used carriers include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions or emulsions areadministered orally, the active ingredient can be suspended or dissolvedin an oily phase combined with emulsifying or suspending agents. Ifdesired, certain sweetening, flavoring, or coloring agents can be added.

A nasal aerosol or inhalation composition can be prepared according totechniques well known in the art of pharmaceutical formulation. Forexample, such a composition can be prepared as a solution in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. A composition havingone or more compounds of the invention can also be administered in theform of suppositories for rectal administration.

The carrier in the pharmaceutical composition must be “acceptable” inthe sense that it is compatible with the active ingredient of thecomposition (and preferably, capable of stabilizing the activeingredient) and not deleterious to the subject to be treated. One ormore solubilizing agents can be utilized as pharmaceutical excipientsfor delivery of a compound of the invention. Examples of other carriersinclude colloidal silicon oxide, magnesium stearate, cellulose, sodiumlauryl sulfate, and D&C Yellow # 10.

The compounds of this invention can be preliminarily screened for theirefficacy in treating an infection with a virus by an in vitro assay (SeeExample 146 below) and then confirmed by animal experiments and clinictrials. Other methods will also be apparent to those of ordinary skillin the art.

The specific examples below are to be construed as merely illustrative,and not limitative of the remainder of the disclosure in any waywhatsoever. Without further elaboration, it is believed that one skilledin the art can, based on the description herein, utilize the presentinvention to its fullest extent. All publications cited herein arehereby incorporated by reference in their entirety.

EXAMPLE 1 Preparation of Compound 1

TMSCl (190 mL, 4.4 eq) was slowly added to a stirred suspension ofL-glutamic acid (50.0 g, 1 eq.) in dry MeOH (1100 mL, 0.3 M) surroundedby an ice-cold bath. After the addition was complete, the ice-clod bathwas removed and the reaction was stirred overnight until TLC showedcompleted conversion. Then, Et₃N (306 mL, 6.5 eq) and (Boc)₂O (82 g, 1.1eq) were added sequentially to the above reaction mixture. The reactionmixture was then stirred until TLC showed complete protection. Thesolvent was removed under reduced pressure. The residue was thenfiltered and washed with Et₂O using a pad of celite. The organic layerswere combined and concentrated. The resulting crude product was purifiedby silica gel column chromatography to afford intermediate 1,N-Boc-L-(+)-glutamic acid dimethyl ester, (88 g, 95%) as an oil: ¹H NMR(CDCl₃) δ 1.40 (s, 9H), 1.91 (m, 1H), 2.14 (m, 2H), 2.37 (m, 2H), 3.64(s, 3H), 3.70 (s, 3H), 4.29 (br, s, 1H). ESI-MS (M+H⁺)=276.

To a solution of intermediate 1 (20 g, 1 eq.) in THF(50 mL) was addeddropwise a solution of lithium hexamethyldisilazide (2.2 eq.) in THF(250 mL) at −78° C. under nitrogen atmosphere. The resulting mixture wasstirred at −78° C. for another 1.5 hours. Bromoacetonitrile (13 g, 1.5eq.) was added dropwise to the above solution over a period of 1 hourwhile maintaining the temperature below −70° C. using a cooling bath.The reaction mixture was stirred at −78° C. for additional for 1-2 hoursand the disappearance of the starting material was confirmed by TLCanalysis. The reaction was then quenched with pre-cooled methanol (10mL) stirred for 10 minutes. The resulting methoxide was then quenchedwith a pre-cooled acetic acid in THF solution (9 mL HOAc/60 mL THF).After stirred for another 10 minutes, the cooling bath was removed andreplaced with water bath. The reaction mixture was allowed to warm up to0±5° C. and then poured into brine solution (10 g of NaCl in 100 mLwater) in a IL extractor. The organic layer was separated andconcentrated to afford a dark brown oil. Silica gel (25 g) and methylenechloride (60 mL) were added to the Rotovap flask and spun on a Rotovapfor 1 hour without heat and vacuum. The slurry was then filtered andwash with another batch of methylene chloride (100 mL). The light brownfiltrate was collected, concentrated, and purified by silica gel columnchromatography to afford intermediate 2 (19 g),2-tert-butoxycarbonyl-amino-4-cyanomethyl-pentanedioic acid dimethylester. ¹H NMR (CDCl₃) δ 1.42 (s, 9H), 2.10-2.17 (m, 2H), 2.77-2.90 (m,3H), 3.73 (s, 3H), 3.74 (s, 3H), 4.32-4.49 (m, 1H), 5.12 (d, J=6.0 Hz,1H). ESI-MS (M+H⁺)=315.

Intermediate 2 (10 g) was dissolved in HOAc (240 mL) and shaken with 10%Pd/C (20 g) under H₂ gas (70 psi) for 2 days. The mixture was filteredover celite. The filtrate was evaporated under reduced pressure and theresidue was repeatedly evaporated from methyl tert-butyl ether to yielda light pink solid. The crude product was dissolved in THF and then Et₃N(20 mL) was added to the solution. The resulting mixture was stirred at60° C. overnight. The reaction was quenched with by addition of H₂O (50mL). The organic layer was separated and the aqueous layer was furtherextracted with methylene chloride. The organic layers were thencombined, concentrated, and purified by silica gel column chromatographyto afford intermediate3,2-tert-butoxycarbonylamino-3-(2-oxo-pyrrolidin-3-yl)-propionic acidmethyl ester. ¹H NMR (CDCl₃) δ 1.37 (s, 9H), 1.75-1.80 (m, 2H),2.04-2.09 (m, 1H), 2.39-2.42 (m, 1H), 3.25-3.29 (m, 2H), 3.67 (s, 3H),4.23-4.26 (m, 1H), 5.47 (d, J=8.0 Hz, 1H), 6.29 (s, 1H). ESI-MS(M+H⁺)=287.

Intermediate 3 (6.0 g, 18.4 mmol) was solved in THF (200 mL) surroundedby an ice bath, followed by addition of 2.0 M LiBH₄/THF (46 ml, 5.0 eq).The ice bath was then removed and the mixture was stirred for 2 hours atroom temperature. To the mixture was sequentialled added water (200 mL),ethyl acetate (200 mL), and MgSO₄ (400 g). Then MgSO₄ was removed andthe aqueous layer was extracted with ethyl acetate. The organic layerswere combined and concentrated to afford intermediate 4,[2-hydroxy-1-(2-oxo-pyrrolidin-3-ylmethyl)-ethyl]-carbamic acidtert-butyl ester, as a white solid (5.2 g, 95%). ESI-MS (M+H⁺)=259.

Triethylamine (0.7 mL) was added to a solution of intermediate 4 (0.59g, 2.28 mmol, 1 eq.) in methylsulfoxide (10.5 mL). The resultingsolution was cooled to 15° C. using an ice-water bath and then sulfurtrioxide-pyridine complex (1.8 g, 5 eq.) was added. The reaction wasstirred at that temperature for 1 hour.(Carboethoxymethylenetriphenyl)-phosphorane (2.4 g, 3 eq.) was added andthe reaction was stirred at ambient temperature for another 3 hours. Thereaction was then quenched by saturated brine (150 mL) and extractedwith ethyl acetate (3×50 mL). The organic layers were combined, driedover anhydrous MgSO₄, filtered, and concentrated to afford a dark redoil. The oil was purified though column chromatography (50% ethylacetate in hexane) to afford intermediate 5,4-tert-butoxycarbonylamino-5-(2-oxo-pyrrolidin-3-yl)-pent-2-enoic acidethyl ester, as a white solid (0.34 g, 45.7%). ¹H NMR (CDCl₃) δ 1.21 (t,3H, J=7.2), 1.36 (s, 9H), 1.48-1.57 (m, 1H), 1.66-1.79 (m, 1H),1.90-1.97 (m, 1H), 2.38-2.47 (m, 2H), 3.26-3.29 (m, 2H), 4.10(q, 2H,J=6.9), 4.27(s, br, 1H), 5.46(d, 1H, J=7.5), 5.87 (d, 1H, J=15.6), 6.78(dd, 1H, J=15.3, J=5.4), 6.98(s, br, 1H). ESI-MS (M+H⁺)=577.

Intermediate 5 (100 mg, 0.3 mmol) was added to a solution of HCl in1,4-dioxane (4.0 M, 3 mL) and the solution was stirred at roomtemperature for 30 minutes. The resulting solution was concentrated byremoving 1,4-dioxane. CH₂Cl₂ (3 mL) was then added to the residue thusobtained and the solution was cooled down to 0-5° C. N-Methylmorpholine(0.13 mL, 4 eq.) was then added and the mixture was stirred for 10minutes to form solution (a). Boc-L-Leu-OH (71 mg, 0.3 mmol) was mixedwith 1,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 70 mg, 1.2eq.) and N-hydroxybenzotriazole (HOBt, 50 mg, 1.2 eq.) in CH₂Cl₂. Themixture was stirred for 20 minutes to form solution (b). Solution (a)was then added to solution (b) and the mixture was stirred at roomtemperature for 2 hours. The reaction residue was added with brine (25mL) and extracted with ethyl acetate (3×15 mL). The organic layers werecombined, dried over anhydrous MgSO₄, and concentrated. The residue waspurified by flash column chromatography (3% MeOH in CH₂Cl₂) to affordintermediate 6,4-(2-tert-butoxycarbonylamino-4-methyl-pentanoylamino)-5-(2-oxo-pyrrolidin-3-yl)-pent-2-enoicacid ethyl ester, as a white solid. ¹H NMR (CDCl₃) δ 0.94 (d, 6H, J=5.1Hz), 1.26 (t, 3H, J=7.2 Hz), 1.43 (s, 9H), 1.66-1.73 (m, 5H), 2.41 (brs, 1H), 3.33 (d, 2H, J=8.1 Hz), 4.16 (q, 2H, J=6.9 Hz), 4.58 (br, s,1H), 5.03 (br, s, 1H), 5.9 (d, 1H, J=15.6 Hz), 6.82 (dd, 1H, J=15.3 Hz,5.1 Hz), 7.50 (br, s, 1H). ESI-MS (M+H⁺)=440.

Intermediate 7 (compound 6) was prepared in 60% yield from2-benzyloxycarbonyl-amino-3-tert-butoxy-butyric acid and intermediate 6using the procedure similar to that described in the precedingparagraph. ¹H NMR (CDCl₃) δ 0.94-0.98 (m, 6H), 1.07 (d, 3H, J=6.3), 1.27(s, 9H), 1.66-1.73 (m, 5H), 2.21-2.50 (m, 2H), 3.20-3.30 (m, 2H), 4.16(q, 2H, J=6.9 Hz), 4.42 (br, s, 1H), 4.58 (br, s, 1H), 5.10 (s, 2H), 5.9(d, 1H, J=15.6 Hz), 6.82 (dd, 1H, J=15.3 Hz, 5.1 Hz), 7.2-7.34 (m, 4H),7.60 (d, 1H), J=7.5 Hz). ESI-MS (M+H⁺)=631.

Compound 1 was prepared by treating intermediate 7 with trifluoroaceticacid (2 mL). ¹H NMR (CDCl₃) δ 0.89-0.93 (m, 6H), 1.13-1.15 (m, 3H),1.22-1.27 (m, 3H), 1.55-1.76 (m, 4H), 1.95-2 (m, 1H), 2.03-2.46 (m, 2H),3.28-3.30 (m, 2H), 4.11-4.18 (m, 3H), 4.33 (br s, 1H), 4.54-4.56 (br s,2H), 5.07 (s, 2H), 5.84-5.94 (d, 1H, J=15.9 Hz), 6.03-6.06 (d, J=7.2Hz), 6.76-6.83 (dd, 1H, J=15.0 Hz, 5.4 Hz), 7.31 (br s, 5H), 8.02 (br s,1H). ESI-MS (M+H⁺)=575.

EXAMPLE 2 Preparation of Compound 2

Compound 2 was prepared in a manner similar to that described in Example1.

¹H NMR (CDCl₃) δ 7.92 (d, J=7.5 Hz, 1H), 7.24-7.38 (m, 5H), 6.78 (dd,J=15, 2.7 Hz, 1H), 5.98 (d, J=7.8 Hz, 1H), 5.89 (d, J=15 Hz, 1H), 5.09(d, J=4.2 Hz, 1H), 5.07 (s, 2H), 4.60-4.78 (m, 1H), 4.43-4.53 (m, 2H),4.21-4.38 (m, 1H), 4.17 (q, J=5.1 Hz, 2H), 3.82-3.88 (m, 1H), 3.40-3.71(m, 2H), 3.29 (m, 2H), 1.40-2.11 (m, 5H), 1.25 (t, J=5.1 Hz), 0.90 (brs, 6H). ESI-MS (M+H⁺)=561.

EXAMPLE 3 Preparation of Compound 3

Compound 3 was prepared in a manner similar to that described in Example1.

¹H NMR(CDCl₃)δ0.91(s, br, 6H), 1.27(t, 3H, J=6.0), 1.60-1.66(m, 5H),1.97-2.44(m, 7H), 3.26(m, 2H), 4.17(q, 2H, J=6.9), 4.24(m, 1H), 4.60(m,1H), 5.06(s, 2H), 5.92(d, 1H,J=15.3), 6.12-6.18(m, 2H), 6.62-6.70(m,1H), 6.83(dd, 1H, J=15.3, 5.), 7.31(s, br, 5H), 7.56(m, 1H), 8.01(m,1H).

ESI-MS (M+Na⁺)=623.9.

EXAMPLE 4 Preparation of Compound 4

Compound 4 was prepared in a manner similar to that described in Example1.

¹H NMR (CDCl₃) δ 7.82 (d, J=8.0 Hz, 1H), 6.90 (d, J=7.5 Hz, 1H), 6.82(dd, J=15, 5.4 Hz, 1H), 5.89 (m, 4H), 5.09 (m, 2H), 4.40-4.68 (m, 2H),4.16 (q, J=7.5 Hz, 2H), 3.32 (m, 2H), 2.03-2.51 (m, 2H), 1.50-2.03 (m,10H), 1.43 (s, 9H), 1.69 (t, J=7.5 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 0.92(d, J=6.0 Hz, 3H).

ESI-MS (M+H⁺)=659.

EXAMPLE 5 Preparation of Compound 5

Compound 5 was prepared in a manner similar to that described in Example1.

¹H NMR (CD₃OD) δ 0.86-1.04 (m, 6H), 1.23 (s, br, 3H), 1.60-1.71 (m, 6H),2.06-2.85 (m, 6H), 3.38 (m, 2H), 4.10-4.28 (m, 2H), 4.34-4.45 (m, 1H),4.60-4.72 (m, 1H), 5.13 (s, 2H), 5.91 (d, 1H, J=15.9), 6.82 (dd, 1H,J=15.9, 4.7), 7.27-7.54 (m, 5H).

ESI-MS (M+H⁺)=589.

EXAMPLE 6 Preparation of Compound 6

Compound 6 was prepared in a manner identical to that of intermediate 7described in Example 1.

¹H NMR (CDCl₃) δ 0.94-0.98 (m, 6H), 1.07 (d, 3H, J=6.3), 1.27 (s, 9H),1.66-1.73 (m, 5H), 2.21-2.50 (m, 2H), 3.20-3.30 (m, 2H), 4.16 (q, 2H,J=6.9 Hz), 4.42 (br, s, 1H), 4.58 (br, s, 1H), 5.10 (s, 2H), 5.9 (d, 1H,J=15.6 Hz), 6.82 (dd, 1H, J=15.3 Hz, 5.1 Hz), 7.2-7.34 (m, 4H), 7.60 (d,1H, J=7.5 Hz).

ESI-MS (M+H⁺)=631.

EXAMPLE 7 Preparation of Compound 7

Compound 7 was prepared in a manner similar to that described in Example1.

¹H NMR (CDCl₃) δ 0.86-0.87 (d, 6H, J=4.2), 1.09 (s, 9H), 1.18-1.22 (t,3H, J=7.2), 1.66 (m, 5H), 2.30 (s, br, 2H), 3.21-3.24 (d, 2H, J=7.2),3.35-3.40 (t, 1H, J=6.6), 3.74-3.76 (d, 1H, J=6.9), 4.10 (q, 2H, J=7.2),4.16 (s, br, 1H), 4.51 (s, br, 2H), 5.03-5.05 (d, 2H, J=4.8), 5.64-5.65(d, 1H, J=15.9), 6.72-6.77 (dd, 1H, J=4.5), 6.93-6.96 (d, 1H, J=6.9),7.28 (s, br, 5H), 7.60 (s, br, 1H).

ESI-MS (M+H⁺)=616.

EXAMPLE 8 Preparation of Compound 8

Compound 8 was prepared in a manner similar to that described in Example1.

¹H NMR (CDCl₃) δ 7.74 (d, J=7.5 Hz, 1H), 7.24-7.33 (m, 10H), 7.05 (d,J=8.5 Hz, 1H), 6.80 (dd, J=15.5, 5.5 Hz, 1H), 6.17 (s, 1H), 5.90 (d,J=15.5 Hz, 1H), 5.73 (d, J=6.5 Hz, 1H), 5.10 (s, 2H), 4.47-4.62 (m, 4H),4.27-4.29 (m, 1H), 4.18-4.20 (m, 3H), 3.24-3.27 (m, 2H), 2.23-2.48 (m,2H), 1.90-2.14 (m, 1H), 1.89 (s, 2H), 1.47-1.73 (m, 3H), 1.26 (t, J=3.6Hz, 3H), 1.21 (d, J=10.2 Hz, 3H), 0.87 (d, J=8.0 Hz, 3H), 0.85 (d, J=8.0Hz 3H).

ESI-MS (M+H⁺)=665.

EXAMPLE 9 Preparation of Compound 9

Compound 9 was prepared in a manner similar to that described in Example1.

ESI-MS (M+H⁺)=639.

EXAMPLE 10 Preparation of Compound 10

Compound 10 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.88-0.98 (m, 6 H), 1.19-1.86 (m, 15H), 2.0-2.08 (m,1H), 2.15-2.39 (m, 2H), 2.47-2.59 (m, 1H), 2.94 (m, 2H), 3.98-4.20 (m,3H), 4.30-4.36 (m, 1H), 4.60-4.64 (m, 1H), 5.09 (m, 2H), 5.89 (d,J=15.6, 1H), 6.89 (dd, 1H, 15.6, 4.8), 7.26-7.33 (m, 5H).

ESI-MS (M+H⁺)=639.

EXAMPLE 11 Preparation of Compound 11

Compound 11 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 7.90 (d, J=7.0 Hz, 1H), 7.31 (s, 5H), 6.77-6.85 (m,2H), 6.41 9 (br, s, 1H), 5.90 (d, J=15 Hz, 1H), 5.78 (d, J=7 Hz, 1H),5.07 (s, 2H), 4.87 (br, s, 1H), 4.41-4.62 (m, 2H), 4.07-4.14 (m, 4H),3.21-3.37 (m, 2H), 2.94-3.18 (m, 2H), 2.28-2.48 (m, 3H), 1.28-2.13 (m,10H), 1.39 (s, 9H), 1.26 (t, 4.5 Hz, 3H), 0.92 (d, J6.3 Hz, 3H), 0.90(d, J=6.3 Hz, 3H)

ESI-MS (M+H⁺)=702.

EXAMPLE 12 Preparation of Compound 12

Compound 12 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=680.

EXAMPLE 13 Preparation of Compound 13

Compound 13 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 7.94 (d, J=7.0 Hz, 1H), 7.31 (s, 5H), 6.81 (dd, J=15,5Hz, 1H), 6.38 (br s, 1H), 5.84-5.93 (m, 2H), 5.31 (br s, 1H), 5.07 (s,2H), 4.41-4.64 (m, 2H), 4.11-4.16 (m, 4H), 3.62-3.64 (m, 2H), 3.60 (s,3H), 3.43-3.51 (m, 2H), 3.23-3.29 (m, 2H), 3.06-3.20 (m, 2H), 2.28-2.48(m, 2H), 1.20-1.96 (m, 8H), 1.26 (t, J=4.5 Hz, 3H), 0.92 (d, J=6.5 Hz,3H), 0.90 (d, J=6.5 Hz, 3H).

ESI-MS (M+H⁺)=660.

EXAMPLE 14 Preparation of Compound 14

Compound 14 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.93 (m, 6H), 1.25-1.30 (m, 3H), 1.47-1.98 (m, 5H),2.20-2.60 (m, 5H), 2.93 (3, 3H), 3.11-3.45 (m, 4H), 4.12-4.19 (m, 2H),4.45-4.48 (m, 3H), 5.09 (s, 2H), 5.86-5.92 (d, 1H, J=15.9 Hz), 6.75-6.82(dd, 1H, J=15.9 Hz, 5.1 Hz), 7.33-7.36 (m, 5H), 8.12 (br, s, 1H), 8.23(br, s, 1H).

ESI-MS (M+H⁺)=637.

EXAMPLE 15 Preparation of Compound 15

Compound 15 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=631.

EXAMPLE 16 Preparation of compound 16

Compound 16 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.81-0.86 (m, 6H), 1.11-1.22 (m, 5H), 1.29-1.34 (m,2H), 1.55-1.77 (m, 9H), 2.37 (s, br, 3H), 2.93 (s, 2H), 3.25 (s, br,2H), 3.62-3.64 (m, 1H), 4.10 (q, 2H, J=6.6), 4.28-4.48 (m, 3H),4.93-5.07 (m, 2H), 5.83 (d, 1H, J=15), 5.99 (s, 1H), 6.75 (dd, 1H,J=16.5, 6.3), 7.26 (s, br, 5H), 7.82 (m, 1H), 8.19 (s, 1H).

EXAMPLE 17 Preparation of Compound 17

Compound 17 was prepared in a manner similar to that described inExample 1.

¹H NMR (CD₃OD) δ 0.92-1.00 (m, 6H), 1.18-1.33 (m, 15H), 1.58-1.82 (m,6H), 2.02-2.35 (m, 4H), 3.20-3.32 (m, 2H), 4.14-4.32 (m, 4H), 4.62-4.66(m, 1H), 5.07-5.13 (m, 2H), 5.29 (d, 1H, J=5.4), 5.92 (d, 1H, J=15.6),6.88 (dd, 1H, J=15.6, 5.7), 7.29-7.36 (m, 5H).

ESI-MS (M+H⁺)=632.

EXAMPLE 18 Preparation of Compound 18

Compound 18 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.90-0.92 (m, 12H), 3.65 (t, 3H, J=6.9), 1.50-1.61 (m,4H), 1.77 (m, 1H), 2.01-2.07 (m, 3H), 2.37 (m, 2H), 3.27-3.36 (m, 2H),3.65 (t, 2H, J=5.4), 3.96(t, 1H, J=6.9), 4.15(q, 2H, J=6.9), 4.30(t, 2H,J=5.4), 4.60(m, 2H), 5.60(d, 1H, J=8.4), 5.89(d, 1H, J=15.6), 6.64(s,1H), 6.80(dd, 1H, J=15.6), 7.07(d, 1H, J=7.76(d, 1H, J=7.5).

ESI-MS (M+H⁺)=545.

EXAMPLE 19 Preparation of Compound 19

Compound 19 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.84-0.89 (m, 12H), 1.15-1.22 (m, 6H), 1.45-1.57 (m,3H), 1.75 (s, br, 3H), 1.94-2.09 (m, 2H), 2.32 (s, br, 2H), 3.27 (d, 2H,J=7.8), 3.87 (t, 1H, J=6.9), 4.00-4.13 (m, 4H), 4.53 (s, br, 2H), 5.20(d, 1H, J=8.4), 5.83 (d, 1H, J=15.3), 6.42 (s, 1H), 6.75 (dd, 1H,J=15.6, 5.4), 6.92 (d, 1H, J=8.1), 7.67 (d, 1H, J=7.2).

ESI-MS (M+H⁺)=533.

EXAMPLE 20 Preparation of Compound 20

Compound 20 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.90-0.93 (m, 18H), 1.24-1.29 (t, 3H, J=5.4 Hz),1.52-2.20 (m, 4H), 2.40 (br, s, 2H), 3.32-3.35 (d, 2H), 3.82-3.84 (m,2H), 3.91-3.96 (t, 1H, J=7.8 Hz), 4.13-4.20 (q, 2H, J=7.5 Hz), 4.58 (brs, 2H), 5.25-5.27 (d, 1H, J=8.1 Hz), 5.89 (d, 1H), J=15.3 Hz), 6.32 (br,s, 1H), 6.81 (dd, 1H, J=15.6 Hz, 5.1 Hz), 6.92 (m, 1H), 7.77 (m, 1H).

ESI-MS (M+H⁺)=539.

EXAMPLE 21 Preparation of Compound 21

Compound 21 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.92-0.96 (m, 12H), 1.27 (t, 3H, J=7.2), 1.43 (s, 9H),2.04-2.11 (m, 2H), 2.38 (s, br, 2H), 3.23-3.35 (m, 2H), 3.83 (t, 1H,J=7.2), 4.16 (q, 2H, J=7.2), 4.61 (m, 2H), 5.00-5.03 (m, 1H,), 5.89 (d,1H, J=15.3), 6.48 (s, br, 1H), 6.81 (dd, 1H, J=15.6, 5.1), 7.00 (m, 1H),7.68 (m, 1H).

ESI-MS (M+H⁺)=539.

EXAMPLE 22 Preparation of Compound 22

Compound 22 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.91 (s, br, 12H), 1.21-1.25 (m, 4H), 1.34-1.36 m, 1H),1.51-1.75 (m, 1H), 2.00-2.13 (m, 2H), 2.34 (m, 2H), 3.26-3.29 (m, 2H),3.64 (s, br, 2H), 3.94-3.96 (m, 1H), 4.15 (q, 2H, J=6.9), 4.22 (m, 2H),4.54 (s, 2H), 4.59 s, 1H), 5.45 (d, 1H, J=7.5), 5.89 (d, 1H, J=15.6),6.61 (s, br, 1H), 6.80 (dd, 1H, J=15.9, 4.5), 7.01 (d, 1H, J=7.2), 7.30(m, 5H), 7.74 (d, 1H, J=7.2).

ESI-MS (M+H⁺)=616.

EXAMPLE 23 Preparation of Compound 23

Compound 23 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=545.

EXAMPLE 24 Preparation of Compound 24

Compound 24 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=558.

EXAMPLE 25 Preparation of Compound 25

Compound 25 was prepared in a manner similar to that described inExample 1.

¹H NMR (CD₃OD) δ 0.95-1.00 (m, 12 H), 1.26-1.29 (m, 6H), 1.57-1.85 (m,5H), 2.03-2.14 (m, 3H), 2.27-2.32 (m, 1H), 2.45-2.52 (m, 1H), 3.93 (s,br, 2H), 4.03-4.04 (m, 1H), 4.16-4.20 (m, 5H), 4.37-4.41 (m, 1H),4.59-4.63 (m, 1H), 5.94 (d, 1H, J=15.6), 6.89 (dd, 1H, J=15.6, 4.5).

ESI-MS (M+H⁺)=568.

EXAMPLE 26 Preparation of Compound 26

Compound 26 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.86-0.96 (m, 12H), 1.27 (t, 3H, J=6.9), 1.49-1.82 (m,10H), 1.95-2.02 (m, 1H), 2.40 (s, br, 2H), 3.32-3.34 (m, 2H), 4.16 (q,2H, J=6.9), 4.55-4.67 (m, 3H), 5.89 (d, 1H, J=15.3), 6.39 (s, br, 1H),6.72 (d, 1H, J=5.4), 6.81 (dd, 2H, J=15.9, 5.1), 7.31-7.76 (m, 5H).

ESI-MS (M+H⁺)=557.

EXAMPLE 27 Preparation of Compound 27

Compound 27 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=690.

EXAMPLE 28 Preparation of Compound 28

Compound 28 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.89-0.94 (m, 6H), 1.22-1.28 (m, 5H), 1.57-2.03 (m,8H), 2.43 (m, 2H), 3.33 (d, 2H, J=6.6), 3.65 (s, 3H), 3.67 (s, 3H), 4.15(q, 2H, J=6.9), 4.26 (m, 1H), 4.44 (m, 1H), 4.60 (m, 1H), 5.28 (s, 1H),5.91 (d, 1H, J=15.6), 6.24-6.29 (m, 1H), 6.82 (dd, 1H, J=15.9, 5.4),7.89 (m, 1H).

ESI-MS (M+H⁺)=542.

EXAMPLE 29 Preparation of Compound 29

Compound 29 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 7.78 (d, J=7.5 Hz, 1H), 7.28 (s, 5H), 7.01 (d, J=7.5Hz, 1H), 6.79 (dd, J=15.5, 5.5 Hz, 1H), 6.50 (s, 1H), 5.89 (d, J=15.5Hz, 1H), 5.38 (d, J=7.0 Hz, 1H), 4.46-4.61 (m, 4H), 4.06-4.21 (m, 4H),3.29 (d, J=9.0 Hz, 2H), 2.35 (br, s, 2H), 2.03 (s, 3H), 1.47-1.72 (m,3H), 1.44 (s, 9H), 1.17-1.28 (m, 6H), 0.88 (d, J=8.4 Hz, 3H), 0.86 (d,J=8.4 Hz 3H).

ESI-MS (M+H⁺)=631.

EXAMPLE 30 Preparation of Compound 30

Compound 30 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=663.

EXAMPLE 31 Preparation of Compound 31

Compound 31 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.84-0.94 (m, 6H), 1.07 (m, 3H), 1.25 (m, 3H), 1.27 (s,9H), 1.44 (s, 9H), 1.66-1.73 (m, 5H), 2.37 (br, s, 1H), 3.33 (d, 2H,J=8.1), 4.08-4.19 (m, 5H), 4.42-4.58 (m, 2H), 5.53-5.16 (d, 1H, J=4.8Hz), 5.87-5.92 (d, 1H, J=15.6 Hz), 6.77-6.84 (dd, 1H, J=15.3 Hz, 5.1Hz), 7.34-7.37 (d, 1H, J=8.1 Hz), 7.650-7.60 (m, 1H).

ESI-MS (M+H⁺)=597.

EXAMPLE 32 Preparation of Compound 32

Compound 32 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=561.

EXAMPLE 33 Preparation of Compound 33

Compound 33 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.83-0.88 (m, 6H), 1.10-1.20 (m, 9H), 1.30-1.35 (t, 2H,J=7.5), 1.57-1.96 (m, 5H), 2.38 (s, br, 2H), 3.02-3.09 (q, 1H, J=7.8),3.27-3.39 (m, 4H), 4.10 (q, 2H, J=6.9), 4.34 (s, br, 2H), 4.50 (m, 1H),4.60 (m, 1H), 4.95 (s, br, 1H), 5.80-5.85 (d, 1H, J=15.6), 6.25 (s, br,1H), 6.73 (dd, 1H, J=4.5), 7.31 (s, br, 1H), 7.69 (s, br, 1H).

ESI-MS (M+H⁺)=527.

EXAMPLE 34 Preparation of Compound 34

Compound 34 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.93 (s, br, 6H), 1.28 (t, 3H, J=6.9), 1.60-2.00 (m,9H), 2.29 (m, 1H), 2.49 (m, 1H), 3.21-3.34 (m, 4H), 3.65-3.69 (m, 6H),4.17 (q, 2H, J=6.6), 4.30 (m, 1H), 4.50 (m, 1H), 4.78 (m, 1H), 5.14 (m,1H), 5.87 (d, 1H, J=15), 6.49-6.56 (m, 1H), 6.80-6.86 (m, 2H).

ESI-MS (M+H⁺)=570.

EXAMPLE 35 Preparation of Compound 35

Compound 35 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.94 (dd, 6H, J=12, 4.8), 1.29 (t, 3H, J=6.9),1.67-2.04 (m, 9H), 2.30-2.50 (m, 2H), 2.94 (s, 3H), 2.96 (s, 3H), 3.18(s, br, 2H), 3.35 (s, br, 2H), 4.05 (m, 1H), 4.18 (q, 2H, J=6.9),4.49-4.52 (m, 1H), 4.61-4.77 (m, 1H), 5.30 (s, 1H), 5.90 (d, 1H,J=15.6), 6.25-6.34 (m, 1H), 6.82 (m, 1H), 7.38 (m, 1H), 7.77 (d, 1H,J=7.5).

ESI-MS (M+H⁺)=610.

EXAMPLE 36 Preparation of Compound 36

Compound 36 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.838 (m, 12H), 1.18 (t, 3H, J=6.3), 1.44-1.68 (m, 5H),2.04-2.10 (m, 3H), 2.28 (m, 2H), 3.20-3.23 (m, 2H), 3.90-3.95 (m, 1H),4.07-4.10 (m, 2H), 4.54 (s, br, 1H), 5.01 (s, 2H), 5.52-5.55 (m, 1H),5.84 (d, 1H, J=15.6), 6.63 (s, 1H), 6.75 (dd, 1H, J=15.6, J=4.8), 7.73(d, 1H, J=6.9).

ESI-MS (M+H⁺)=573.

EXAMPLE 37 Preparation of Compound 37

Compound 37 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.89 (m, 6H), 1.23 (t, 3H, J=10.2), 1.45-1.99 (m, 6H),2.36-2.58 (m, 2H), 2.94-3.09 (m, 2H), 3.26-3.34 (m, 2H), 4.10-4.20 (m,3H), 4.44-4.54 (m, 2H), 5.04 (s, 2H), 5.89 (d, 1H, J=15.3), 6.79 (dd,1H, J=15.3, 4.8), 7.16-7.30 (m,

ESI-MS (M+H⁺)=621.

EXAMPLE 38 Preparation of Compound 38

Compound 38 was prepared in a manner similar to that described inExample 1.

¹H NMR (CD₃OD) δ 0.79-0.91 (m, 6 H), 1.20-1.28 (m, 3H), 1.45-1.83 (m,6H), 2.32-2.53 (m, 2H), 2.92-3.24 (m, 4H), 4.10-4.20 (m, 2H), 4.41-4.58(m, 3H), 5.13 (s, 2H), 5.91 (dd, 1H, J=15.6, 1.5), 6.77-6.91 (m, 3H),7.18-7.32 (m, 7H).

ESI-MS (M+H⁺)=637.

EXAMPLE 39 Preparation of Compound 39

Compound 39 was prepared in a manner similar to that described inExample 1.

¹H NMR (CD₃OD) δ 0.79-0.91 (m, 6 H), 1.20-1.28 (m, 3H), 1.45-1.83 (m,6H), 2.36-2.57 (m, 2H), 2.92-3.24 (m, 4H), 4.10-4.20 (m, 2H), 4.41-4.58(m, 3H), 5.13 (s, 2H), 5.91 (dd, 1H, J=15.6, 1.5), 6.82-6.91 (m, 3H),7.21-7.35 (m, 7H).

ESI-MS (M+H⁺)=639.

EXAMPLE 40 Preparation of Compound 40

Compound 40 was prepared in a manner similar to that described inExample 1.

¹H NMR (CD₃OD) δ 0.79-0.90 (m, 6 H), 1.20-1.29 (m, 3H), 1.45-1.83 (m,6H), 2.36-2.57 (m, 2H), 2.94-3.10 (m, 2H), 3.26-3.34 (m, 2H), 4.10-4.20(m, 2), 4.44-4.61 (m, 3H), 5.10 (s, 2H), 5.90 (dd, 1H, J=15.6, 1.5),6.83-6.94 (m, 4H), 7.24-7.32 (m, 5H).

ESI-MS (M+H⁺)=657.

EXAMPLE 41 Preparation of Compound 41

Compound 41 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.79 (s, br, 6H), 1.12-1.22 (m, 7H), 1.38-1.96 (m, 3H),2.32 (s, br, 1H), 2.90-3.05 (m, 2H), 3.21 (m, 2H), 4.10 (q, 2H, J=6.9),4.37-4.58 (m, 3H), 4.95-5.02 (m, 3H), 5.85 (d, 1H, J=15.9), 6.17-6.18(m, 2H), 6.70-6.77 (m, 2H), 7.03 (m, 1H), 7.25 (s, br, 5H), 7.54 (s,1H), 8.16 (d, 1H, J=7.2).

ESI-MS (M+H⁺)=610.

EXAMPLE 42 Preparation of Compound 42

Compound 42 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=711.

EXAMPLE 43 Preparation of Compound 43

Compound 43 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.69-0.83 (m, 6H), 1.21 (t, 3H, J=6.9), 1.29 (d,1H,J=5.1), 1.44 (m, 1H), 1.86-2.23 (m, 6H), 2.97-2.99 (m, 2H), 3.13-3.21(m, 2H), 3.88 (s, 1H), 4.09 (q, 2H, J=6.9), 4.43 (m, 1H), 4.71-4.77 (m,1H), 5.02 (s, 2H), 5.36-5.40 (m, 1H), 5.65 (d, 1H, J=15.9), 6.61 (dd,1H, J=15.3, J=4.5), 7.08-7.26 (m, 10H), 7.46-7.49 (m, 1H).

ESI-MS (M+H⁺)=607.

EXAMPLE 44 Preparation of Compound 44

Compound 44 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=579.

EXAMPLE 45 Preparation of Compound 45

Compound 45 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 7.83 (d, J=8 Hz, 1H), 7.28-7.36 (m, 5H), 6.81 (dd,J=16, 6 Hz, 1H), 6.47 (s, 1H), 5.91 (d, J=15 Hz, 1H), 5.53 (d, J=8 Hz,1H), 5.07-5.13 (m, 2H), 4.60-4.68 (m, 2H), 4.13 (q, J=7 Hz, 2H), 3.97(dd, J=8, 3.6 Hz, 1H), 3.28-3.31 (m, 2H), 2.49 (t, J=7 Hz, 2H),2.29-2.42 (m, 2H), 1.90-2.21 (m, 6H), 2.06 (s, 3H), 1.76 (m, 1H), 1.60(m, 1H), 1.26 (t, J=7 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H) 0.91 (d, J=6.9 Hz,3H).

ESI-MS (M+H⁺)=591.

EXAMPLE 46 Preparation of Compound 46

Compound 46 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 7.75 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H),7.24-7.52 (m, 5H), 6.82 (dd, J=15, 5 Hz, 1H), 6.54 (s, 1H), 5.89 (dd,J=15, 1.8 Hz, 1H), 5.42 (d, J=7 Hz, 1H), 5.02-5.12 (m, 2H), 4.60-4.67(m, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.28-3.30 (m, 2H), 2.49 (t, J=7.5 Hz,2H), 2.33-2.43 (m, 2H), 1.90-2.14 (m, 6H), 2.06 (s, 3H), 1.46-1.79 (m,3H), 1.26 (t, J=7.2 Hz, 3H) 0.92 (d, J=1.5 Hz, 6H).

ESI-MS (M+H⁺)=605.

EXAMPLE 47 Preparation of Compound 47

Compound 47 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=639.

EXAMPLE 48 Preparation of Compound 48

Compound 48 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=546.

EXAMPLE 49 Preparation of Compound 49

Compound 49 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 1.26 (t, 3H, J=6.9), 1.55-1.63 (m, 1H), 1.75-1.82 (m,1H), 1.94-2.02 (m, 1H), 2.22-2.31 (m, 1H), 2.41-2.51 (m, 1H), 3.59-3.60(m, 1H), 3.68-3.73 (m, 1H), 3.82-3.87 (m, 2H), 4.15 (q, 2H, J=6.9),4.27-4.29 (m, 1H), 4.44-4.50 (m, 1H), 4.63 (s, br, 1H), 5.10 (s, 2H),5.95 (d, 1H, J=15.6), 6.85 (dd, 1H, J=15.6, 4.5), 7.2-7.34 (m, 4H), 8.16(d, 1H, J=8.7).

ESI-MS (M+H⁺)=571.

EXAMPLE 50 Preparation of Compound 50

Compound 50 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=594.

EXAMPLE 51 Preparation of Compound 51

Compound 51 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.88 (s, br, 6H), 1.18-1.77 (m, 12H), 2.38 (m, 1H),2.93 (s, 3H), 2.97 (s, 3H), 3.29 (m, 2H), 4.10 (q, 2H, J=6.9), 4.49 (m,2H), 5.15-5.21 (m, 1H), 5.37 (q, 1H, J=5.7), 5.80-5.85 (m, 2H), 6.07 (s,br, 1H), 6.73 (dd, 1H, J=15, 5.4), 7.29 (d, 1H, J=8.7), 7,82 (m, 1H),8.70 (m, 1H).

ESI-MS (M+H⁺)=596.

EXAMPLE 52 Preparation of Compound 52

Compound 52 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.83-0.87 (m, 6H), 1.14 (s, 6H), 1.16-1.20 (m, 6H),1.42-1.67 (m, 6H), 2.22-2.26 (m, 2H), 3.32-4.10 (m, 4H), 4.47 (br, s,2H), 5.80-5.85 (d, 1H, J=15.3 Hz), 6.70-6.77 (dd, 1H, J=15.3 Hz, 5.1Hz), 7.79-7.87 (br, s, 2H).

ESI-MS (M+H⁺)=497.

EXAMPLE 53 Preparation of Compound 53

Compound 53 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.96 (s, br, 6H), 1.16-1.30 (m, 15H), 1.62-2.02 (m,6H), 2.33-2.46 (m, 2H), 2.98 (d, 3H, J=8.7), 3.34 (s, br, 2H), 3.88-3.91(m, 1H), 4.14-4.19 (m, 3H), 4.40 (m, 1H), 4.60-4.76 (m, 1H), 5.76-6.14(m, 3H), 6.81 (d, 1H, J=15), 7.60 (m, 1H).

ESI-MS (M+H⁺)=575.

EXAMPLE 54 Preparation of Compound 54

Compound 54 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.97 (t, 6H, J=0.8), 1.08 (d, 3H, J=5.7), 1.28 (s, b,12H), 1.55-1.86 (m, 6H), 2.05 (m, 1H), 2.42 (m, 2H), 3.31 (d, 2H,J=8.1), 4.14-4.25 (m, 5H), 4.37-4.45 (m, 3H), 4.60 (m, 1H), 5.91-6.10(m, 3H), 6.83 (dd, 1H, J=15.6, 4.5), 7.26-7.76 (m, 9H).

ESI-MS (M+H⁺)=719.

EXAMPLE 55 Preparation of Compound 55

Compound 55 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.96-0.99 (m, 6H), 1.14 (d, 3H, J=6.6), 1.24 (s, 9H),1.28 (t, 3H, J=6.9), 1.39 (t, 3H, J=6.9), 1.58-2.04 (m, 5H), 2.35-2.40(m, 2H), 3.05 (q, 2H, J=7.5), 3.31-3.34 (m, 2H), 3.87-3.89 (m, 1H),4.09-4.10 (m, 1H), 4.17 (q, 2H, J=7.2), 4.41 (m, 1H), 4.59 (m, 1H), 4.74(m, 1H), 5.73 (d, 1H, J=6.0), 5.84-5.96 (m, 1H), 6.22 (s, 1H), 6.41 (q,1H, J=15.9, 4.8), 7.57-7.60 (m, 1H), 7.69 (d, 1H, J=7.2).

ESI-MS (M+H⁺)=589.

EXAMPLE 56 Preparation of Compound 56

Compound 56 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=603.

EXAMPLE 57 Preparation of Compound 57

Compound 57 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.85-0.90 (m, 6H), 1.27 (t, 3H, J=7.2 Hz), 1.60-1.66(m, 5H), 2.33 (m, 1H), 2.79 (m, 1H), 2.94 (m, 1H), 3.20 (m, 2H), 4.17(q, 2H, J=6.9 Hz), 4.39 (m, 1H), 4.55 (m, 2H), 5.10 (s, 2H), 5.91 (d,1H, J=15.9 Hz), 6.40 (m, 1H), 6.85 (dd, 1H, J=15.9, 5.1 Hz), 7.31 (m,20H), 7.84 (m, 1H).

ESI-MS (M+H⁺)=637.

EXAMPLE 58 Preparation of Compound 58

Compound 58 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.88-0.94 (m, 6H), 1.27 (t, 3H, J=7.2 Hz), 1.60-1.66(m, 5H), 2.07 (m, 1H), 2.43 (m, 2H), 2.72-2.80 (m, 2H), 3.30 (m, 2H),4.17 (q, 2H, J=6.9 Hz), 4.39 (m, 1H), 4.55 (m, 2H), 5.10 (s, 2H), 5.91(d, 1H, J=15.9 Hz), 6.10-6.20 (m, 2H), 6.30 (m, 2H), 6.85 (dd, 1H,J=15.9, 5.1 Hz), 7.31 (m, 5H), 7.60 (m, 1H).

ESI-MS (M+H⁺)=588.

EXAMPLE 59 Preparation of Compound 59

Compound 59 was prepared in a manner similar to that described inExample 1.

¹H NMR (CD₃OD) δ 0.86-1.04 (m, 6H), 1.21-1.52 (m, 12H), 1.61-1.71 (m,6H), 2.06-2.86 (m, 6H), 3.40 (m, 2H), 4.10-4.27 (m, 2H), 4.34-4.45 (m,1H), 4.60-4.72 (m, 1H), 5.13 (s, 2H), 5.90 (d, 1H, J=15.6), 6.81 (dd,1H, J=15.6, 4.8), 7.27-7.54 (m, 5H).

ESI-MS (M+H⁺)=645.

EXAMPLE 60 Preparation of Compound 60

Compound 60 was prepared in a manner similar to that described inExample 1.

¹H NMR (CD₃OD) δ 0.92-1.00 (m, 6H), 1.19-1.23 (m, 6H), 1.57-1.80 (m,6H), 2.03-2.36 (m, 4H), 3.19-3.31 (m, 2H), 4.16-4.34 (m, 4H), 4.58-4.62(m, 1H), 5.04-5.11 (m, 2H), 5.24 (d, 1H, J=5.1), 5.91 (d, 1H, J=15.3),6.89 (dd, 1H, J=15.3, 5.4), 7.30-7.35 (m, 5H).

ESI-MS (M+H⁺)=576.

EXAMPLE 61 Preparation of Compound 61

Compound 61 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=576.

EXAMPLE 62 Preparation of Compound 62

Compound 62 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=617.

EXAMPLE 63 Preparation of Compound 63

Compound 63 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+Na⁺)=867.

EXAMPLE 64 Preparation of Compound 64

Compound 64 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.94-0.99 (m, 6H), 1.07 (m, 3H), 1.28 (m, 15H), 1.60(m, 3H), 2.10 (br, s, 2H), 2.29 (br, s, 2H), 3.32-3.35 (d, 2H), 4.09 (m,6H), 4.32 (br, s, 1H), 4.60 (br, s, 1H), 5.76 (m, 1H), 5.84-5.89 (d, 1H,J=14.7 Hz), 5.98 (br, s, 1H), 6.81 (dd, 1H, J=15.9 Hz, 5.4 Hz), 7.38 (m,1H), 7.60 (m, 1H).

ESI-MS (M+H⁺)=569.

EXAMPLE 65 Preparation of Compound 65

Compound 65 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.94-0.99 (m, 6H), 1.28 (t, 3H, J=6.9), 1.75-1.82 (m,2H), 2.10-2.33 (m, 3H), 3.03-3.15 (m, 2H), 3.22-3.31 (m, 2H), 4.16 (q,2H, J=7.5), 4.39-4.51 (m, 2H), 4.80-4.83 (m, 1H), 5.77 (d, 1H, J=15.6),5.96 (s, 1H), 6.66-6.74 (m, 2H), 7.15-7.62 (m, 10H), 7.7 (d, 2H, J=8.1).

ESI-MS (M+H⁺)=577.

EXAMPLE 66 Preparation of Compound 66

Compound 66 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=630.

EXAMPLE 67 Preparation of Compound 67

Compound 67 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.91 (s, br, 6H), 1.26 (t, 3H, J=6.9), 1.42 (s, 18H),1.56-1.63 (m, 5H), 1.80-1.82 (m, 2H), 2.04 (m, 1H), 2.35-2.41 (m, 3H),3.12 (s, br, 2H), 3.32 (s, br, 2H), 4.16 (m, 3H), 4.54 (s, br, 2H), 5.89(d, 1H, J=15.6), 6.81(m, 2H).

ESI-MS (M+H⁺)=654.

EXAMPLE 68 Preparation of Compound 68

Compound 68 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=809.

EXAMPLE 69 Preparation of Compound 69

Compound 69 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=557.

EXAMPLE 70 Preparation of Compound 70

Compound 70 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=547.

EXAMPLE 71 Preparation of Compound 71

Compound 71 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=562.

EXAMPLE 72 Preparation of Compound 72

Compound 72 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=605.

EXAMPLE 73 Preparation of Compound 73

Compound 73 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=600.

EXAMPLE 74 Preparation of Compound 74

Compound 74 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.88-0.98 (m, 6 H), 1.19-1.86 (m, 15H), 2.0-2.08 (m,1H), 2.15-2.39 (m, 2H), 2.47-2.59 (m, 1H), 2.94 (m, 2H), 3.98-4.20 (m,3H), 4.30-4.36 (m, 1H), 4.60-4.64 (m, 1H), 5.09 (m, 2H), 5.89 (d, 1H,J=15.6), 6.89 (dd, 1H, 15.6, 4.8), 7.26-7.33 (m, 5H).

ESI-MS (M+H⁺)=602.

EXAMPLE 75 Preparation of Compound 75

Compound 75 was prepared in a manner similar to that described inExample 1.

¹H NMR(CDCl₃) δ 0.89-0.93(m, 6H), 1.13-1.15(m, 3H), 1.22-1.27(m, 3H),1.55-1.76(m, 4H), 1.95-2.0-2(m, 1H), 2.03-2.46(m, 2H), 3.28-3.30(m, 2H),4.11-4.18(m, 3H), 4.33(br s, 1H), 4.54-4.56(br s, 2H), 5.07(s, 2H),5.84-5.94(d, 1H, J=15.9 Hz), 6.03-6.06(d, J=7.2 Hz), 6.76-6.83(dd, 1H,J=15.0 Hz, 5.4 Hz), 7.31(br s, 5H), 8.02(br s, 1H).

ESI-MS (M+H⁺)=575.

EXAMPLE 76 Preparation of Compound 76

Compound 76 was prepared as follows: Compound 74 (0.047 g, 0.11 mmol)was dissolved in CH₂Cl₂ (1.5 ml). Et₃N (0.037 ml, 3.0 eq.) was thenadded to the above solution. The resultant solution was stirred at roomtemperature for 30 minutes. Methyl chloroformate (0.013 ml, 1.5 eq.) wassubsequently added. The reaction mixture was stirred at room temperaturefor another 20 hours and then concentrated to afford a residue. Theresidue was purified by flash column chromatography (5% MeOH in CH₂Cl₂)to afford compound 76 as a white solid (64 mg, 85%).

¹H NMR (CDCl₃) δ 0.88-0.98 (m, 6 H), 1.19-1.83 (m, 15H), 2.0-2.08 (m,1H), 2.15-2.38 (m, 2H), 2.47-2.59 (m, 1H), 3.07 (m, 2H), 3.59 (s, 3H),3.98-4.20 (m, 3H), 4.310-4.36 (m, 1H), 4.60-4.64 (m, 1H), 5.08 (m, 2H),5.88 (d, 1H, J=15.6), 6.89 (dd, 1H, 15.6, 4.8), 7.27-7.32 (m, 5H).

ESI-MS (M+H⁺)=660.

EXAMPLE 77 Preparation of Compound 77

Compound 77 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=523.

EXAMPLE 78 Preparation of Compound 78

Compound 78 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=557.

EXAMPLE 79 Preparation of Compound 79

Compound 79 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=423.

EXAMPLE 80 Preparation of Compound 80

Compound 80 was prepared as follows: Compound 59 (0.023 g, 0.036 mmol)was added to a solution of HCl in 1,4-dioxane (4.0 M, 2 ml). Thesolution was stirred at room temperature for 30 minutes and thenconcentrated to give compound 80 as a white solid (21 mg, 99%);

¹H NMR (CD₃OD) δ 0.86-1.04 (m, 6H), 1.23 (s, br, 3H), 1.60-1.71 (m, 6H),2.06-2.85 (m, 6H), 3.38 (m, 2H), 4.10-4.28 (m, 2H), 4.34-4.45 (m, 1H),4.60-4.72 (m, 1H), 5.13 (s, 2H), 5.91 (d, 1H, J=15.9), 6.82 (dd, 1H,J=15.9, 4.7), 7.27-7.54 (m, 5H).

ESI-MS (M+H⁺)=589.

EXAMPLE 81 Preparation of Compound 81

Compound 81 was prepared in 20% yield from compound 52 and methylchloroformate.

¹H NMR(CDCl₃) δ 0.94-0.99 (m, 6H), 1.07 (m, 3H), 1.28 (m, 12H), 1.60 (m,3H), 2.10 (br s, 2H), 2.29 (br s, 2H), 3.32-3.35 (d, 2H), 3.69 (s, 3H),4.18 (m, 4H), 4.39 (br s, 1H), 4.61 (br s, 1H), 5.59-5.81 (m, 2H),5.89-5.95 (d, 1H, J=16.2 Hz), 6.82 (dd, 1H, J=15.3 Hz, 5.7 Hz), 7.34 (m,1H), 7.56 (m, 1H).

ESI-MS (M+H⁺)=555.

EXAMPLE 82 Preparation of Compound 82

Compound 82 was prepared in a manner similar to that described inExample 1.

¹H NMR(CDCl₃) δ 0.95 (m, 6H), 1.02-1.04 (m, 3H), 1.27 (s, 12H),1.56-1.82 (m, 5H), 2.03 (s, 3H), 2.18 (m, 1H), 2.40 (m, 2H), 3.31-3.34(m, 2H), 4.15-4.18 (m, 3H), 4.36 (m, 1H), 4.46 (m, 1H), 4.61 (m, 1H),5.92 (d, 1H, J=15 Hz), 6.38 (s, 1H), 6.63 (s, 1H), 6.82 (d, 1H, J=15Hz), 7.53 (d, 1H, J=6 Hz), 7.65 (d, 1H, J=6 Hz).

ESI-MS (M+H¹)=539.

EXAMPLE 83 Preparation of Compound 83

Compound 83 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.96 (t, 6H, J=6 Hz), 1.08 (d, 3H, J=6 Hz), 1.26 (s,9H), 1.54-2.42 (m, 8H), 3.35 (d, 2H, J=9 Hz), 3.68 (t, 2H, J=6 Hz),4.14-4.18 (m, 4H), 4.27-4.38 (m, 2H), 4.45 (br, 1H), 4.60 (br, 1H), 5.92(d, 2H, J=15 Hz), 6.32 (s, 1H), 6.83 (s, 1H), 6.83 (dd, 1H, J=15.0 Hz,6.0 Hz), 7.39 (d, 1H, J=6 Hz), 7.66 (d, 1H, J=6 Hz).

ESI-MS (M+Na⁺)=625.

EXAMPLE 84 Preparation of Compound 84

Compound 84 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.97 (q, 6H, J=6 Hz), 1.13 (d, 3H, J=6 Hz), 1.26 (s,12H), 1.55-2.06 (m, 6H), 2.41 (br, 2H), 3.32 (d, 2H, J=9 Hz), 4.04-4.09(m, 2H), 4.18 (q, 2H, J=6 Hz), 4.41 (br, 1H), 4.59 (br, 1H), 5.93 (d,1H, J=15 Hz), 6.32 (s, 1H), 6.83 (dd, 1H, J=15.0 Hz, 6.0 Hz), 7.02 (d,1H, J=6 Hz), 7.58 (d, 1H, J=6 Hz), 7.79 (d, 1H, J=6 Hz).

ESI-MS (M+H⁺)=629.

EXAMPLE 85 Preparation of Compound 85

Compound 85 was prepared in a manner similar to that described inExample 1 in a 68% yield.

¹H NMR (CDCl₃) δ 7.83 (d, J=8 Hz, 1H), 7.28-7.36 (m, 5H), 6.81 (dd,J=16, 6 Hz, 1H), 6.47 (s, 1H), 5.91 (d, J=15 Hz, 1H), 5.53 (d, J=8 Hz,1H), 5.07-5.13 (m, 2H), 4.60-4.68 (m, 2H), 4.13 (m, 3H), 3.97 (dd, J=8,3.6 Hz, 1H), 3.28-3.31 (m, 2H), 2.49 (t, J=7 Hz, 2H), 2.29-2.42 (m, 2H),1.90-2.21 (m, 6H), 2.06 (s, 3H), 1.76 (m, 1H), 1.26 (m, 12H), 0.95 (d,J=6.9 Hz, 3H).

ESI-MS (M+H⁺)=649.

EXAMPLE 86 Preparation of Compound 86

Compound 86 was prepared in a manner similar to that described inExample 1 in a 57% yield.

¹H NMR (CDCl₃) δ 7.83 (d, J=8 Hz, 1H), 7.28-7.36 (m, 5H), 6.81 (dd,J=16, 6 Hz, 1H), 6.47 (s, 1H), 5.91 (d, J=15 Hz, 1H), 5.53 (d, J=8 Hz,1H), 5.07-5.13 (m, 2H), 4.60-4.68 (m, 2H), 4.13 (q, J=7 Hz, 2H), 3.97(dd, J=8, 3.6 Hz, 1H), 3.28-3.31 (m, 2H), 2.06-2.86 (m, 6H), 1.90-2.21(m, 6H), 2.06 (s, 3H), 1.76 (m, 1H), 1.21-1.52 (m, 12H).

ESI-MS (M+H⁺)=663.

EXAMPLE 87 Preparation of Compound 87

Compound 87 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.98 (d, 6H, J=6 Hz), 1.09 (s, 12H), 1.27 (t, 3H, J=6Hz), 1.50-2.49 (m, 8H), 3.32 (q, 2H, J=3 Hz), 3.63 (q, 1H, J=3 Hz),3.87-3.90 (m, 1H), 4.16 (q, 2H, J=6 Hz), 4.29-4.45 (m, 1H), 4.77 (m,1H), 5.84 (br, 1H), 5.93 (d, 1H, J=15 Hz), 6.12 (d, 1H, J=6 Hz), 6.81(dd, 1H, J=15.0 Hz, 6.0 Hz), 7.33-7.44 (m, 5H), 8.48 (d, 1H, J=9 Hz).

ESI-MS(M+H⁺)=65 1.

EXAMPLE 88 Preparation of Compound 88

Compound 88 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.91-0.96 (m, 6H), 1.04-1.06 (m, 3H), 1.23 (m, 12H),1.51-2.05 (m, 8H), 2.40 (br s, 2H), 3.30 (m, 2H), 4.15 (m, 4H), 4.39 (m,1H), 4.54 (m, 2H), 5.19-5.32 (m, 2H), 5.84-5.97 (m, 3H), 6.82 (dd, 1H,J=15.6 Hz, 5.4 Hz), 7.35 (m, 1H), 7.60(m, 1H).

ESI-MS (M+H⁺)=581.

EXAMPLE 89 Preparation of Compound 89

Compound 89 was prepared in a 85% yield by reacting compound 1 withpivaloyl chloride in the presence of Et₃N and DMAP.

¹H NMR (CDCl₃) δ 0.94-0.98 (m, 6H), 1.08 (d, J=6.3 Hz, 3H), 1.25 (s,9H), 1.66-1.73 (m, 5H), 2.21-2.50 (m, 2H), 3.20-3.30 (m, 2H), 4.16 (q,J=6.9 Hz, 2H), 4.42 (br, 1H), 4.58 (br, 1H), 5.10 (s, 2H), 5.9 (d,J=15.6 Hz, 1H), 6.82 (dd, J=15.3 Hz, 5.1 Hz, 1H), 7.2-7.34 (m, 4H), 7.60(d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=659.

EXAMPLE 90 Preparation of Compound 90

Compound 6 was dissolved in an 1N NaOH/EtOH solution. The mixture wasstirred for 1 hour and concentrated to afford a residue. The residue waspurified by column chromatography to give compound 90 in a 20% yield.

¹H NMR (CDCl₃) δ 0.83-0.93 (m, 6H), 1.02-1.04 (d, 4H, J=5.7 Hz),1.16-1.31 (m, 11H), 1.52-1.74 (m, 5H), 2.0 (m, 1H), 2.30-2.43 (m, 2H),3.24-3.26 (m, 2H), 4.15 (m, 2H), 4.41 (br s, 1H), 4.63 (br s 1H), 5.08(s, 2H), 5.9 (m, 1H), 6.82 (m, 1H), 7.29-7.33 (m, 5H), 7.47 (d, 1H,J=8.1 Hz), 7.69 (m, 1H).

ESI-MS (M+H⁺)=603.

EXAMPLE 91 Preparation of Compound 91

Compound 91 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.93 (q, 6H, J=3 Hz), 1.05 (d, 3H, J=6 Hz), 1.21-1.24(m, 15H), 1.42-2.05 (m, 6H), 2.38 (br, 2H), 3.26-3.29 (m, 2H), 4.15 (br,2H), 4.39 (m, 1H), 4.57 (m, 1H), 4.97-5.14 (m, 3H), 5.85-5.90 (m, 3H),6.78 (dd, 1H, J=15.6 Hz, 5.4 Hz), 7.34 (m, 5H), 7.57 (d, 1H, J=7.2 Hz).

ESI-MS (M+H⁺)=645.

EXAMPLE 92 Preparation of Compound 92

Compound 92 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.93-0.98 (m, 6H), 1.10 (d, 3H, J=6.3), 1.25 (s, 9H),1.55-1.68 (m, 9H), 2.40 (m, 3H), 3.30-3.39 (m, 2H), 4.10-4.20 (m, 4H),4.26-4.36 (m, 1H), 4.25-4.58 (m, 1H), 5.10 (q, 2H, J=12), 5.49 (d, 1H,J=16.5), 5.64 (s, 1H), 5.84 (d, 1H, J=5.4), 6.59 (dd, J=16.5, 5.0H),7.29-7.34 (m, 5H), 7.96 (d, J=6.0).

ESI-MS (M+H⁺)=584.1.

EXAMPLE 93 Preparation of Compound 93

Compound 93 was prepared in a manner similar to that described inExample 1 in a 66% yield.

¹H NMR (CDCl₃) δ 0.86-095 (m, 6H), 1.22 (m, 4H), 1.41 (m, 11H),1.55-1.90 (m, 9H), 2.32 (m, 2H), 3.25-3.35 (m, 3H), 3.39 (m, 1H),4.11-4.19 (m, 2H), 4.34-4.47 (m, 2H), 4.85 (m, 1H), 5.08 (s, 2H), 5.84(m, 2H), 6.09 (m, 1H), 6.73-6.75 (m, 1H), 7.73 (m, 1H).

ESI-MS(M+H⁺)=707

EXAMPLE 94 Preparation of Compound 94

Compound 94 was prepared as follows: Compound 93 was added into asolution of HCl in 1,4-dioxane. The mixture was stirred at roomtemperature for 30 minutes and concentrated. CH₂Cl₂ was then added tothe resultant residue and the mixture was cooled down to 0-5° C.N-methylmorpholine was added into the mixture, which was then stirredfor 10 minutes. Benzochloromate was subsequently added to the solution,which was stirred at room temperature for another 2 hours to give acrude product. The crude product was purified by flash columnchromatography to give compound 94.

¹H NMR (CDCl₃) δ 0.86-095 (m, 6H), 1.22 (m, 4H), 1.41 (m, 11H),1.55-1.90 (m, 9H), 2.32 (m, 2H), 3.25-3.35 (m, 3H), 3.39 (m, 1H),4.11-4.19 (m, 2H), 4.34-4.47 (m, 2H), 4.85 (m, 1H), 5.84 (m, 2H), 6.09(m, 1H), 6.73-6.75 (m, 1H), 7.73 (m, 5H).

ESI-MS (M+H⁺)=585.

EXAMPLE 95 Preparation of Compound 95

Compound 95 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.93-0.98 (m, 6H), 1.07 (d, 3H, J=5.4), 1.27 (s, 9H),1.52-2.10 (m, 8H), 2.40 (m, 2H), 3.23 (s, 3H), 3.28-3.31 (m, 2H), 3.68(s, 3H), 4.16 (m, 2H), 4.44-4.45 (m, 1H), 4.63-4.64 (m, 1H), 5.10 (q,2H, J=6), 5.90 (d, 1H, J=4.5), 6.51 (d, 1H, J=15.6), 6.83 (dd, 1H,J=5.1, 15.3), 7.35 (m, 5H), 7.57-7.62 (m, 1H).

ESI-MS (M+H⁺)=646.

EXAMPLE 96 Preparation of Compound 96

Compound 96 was prepared in a manner similar to that described inExample 1 in a 38% yield.

¹H NMR (CDCl₃) δ 0.95 (q, 6H, J=8.4 Hz), 1.09 (d, 3H, J=6.3 Hz), 1.17(d, 6H, J=6.6 Hz), 1.26 (s, 9H), 1.52-1.82 (m, 5H), 1.99-2.06 (m, 1H),2.38 (br, 2H), 3.27-3.30 (m, 2H), 4.06-4.21 (m, 3H), 4.41 (m, 1H), 4.61(m, 1H), 5.11 (q, 2H, J=3 Hz), 5.65 (d, 1H, J=7.8), 5.84-5.89 (m, 3H),6.66 (dd, 1H, J=14.7 Hz, 5.4 Hz), 7.29-7.35 (m, 5H), 7.47 (d, 1H, J=7.8Hz).

ESI-MS(M+H⁺)=644.

EXAMPLE 97 Preparation of Compound 97

Compound 97 was prepared in a manner similar to that described inExample 1 in a 71% yield.

¹H NMR(CDCl₃) δ 0.25 (q, 2H, J=5.4 Hz), 0.50-0.56 (m, 2H), 0.93 (q, 6H,J=2.1 Hz), 1.03-1.18 (m, 4H), 1.24 (s, 9H), 1.50-2.07 (m, 7H), 2.36-2.41(m, 2H), 3.25-3.28 (m, 2H), 3.92 (d, 2H, J=7.2 Hz), 4.14-4.16 (m, 2H),4.40-4.45 (m, 1H), 4.58 (m, 1H), 5.08 (q, 2H, J=6.6 Hz), 5.87 (d, 1H,J=5.1 Hz), 5.93 (d, 1H, J=15.6 Hz), 6.08 (s, 1H), 6.82 (dd, 1H, J=15.9Hz, 5.4 Hz), 7.29-7.38 (m, 5H), 7.63 (d, 1H, J=7.5 Hz).

ESI-MS (M+Na⁺)=679.

EXAMPLE 98 Preparation of Compound 98

Compound 98 was prepared in a manner similar to that described inExample 1 in a 50% yield.

¹H NMR (CDCl₃) δ 0.85-098 (m, 6H), 1.06 (m, 4H), 1.26 (s, 9H), 1.44-1.63(m, 9H), 1.75-1.80 (m, 7H), 2.05-2.34 (m, 2H), 3.27-3.29 (m, 2H),3.70-3.72 (m, 1H), 4.14 (m, 2H), 4.42 (m, 1H), 4.59 (m, 1H), 5.08 (s,2H), 5.88-5.98 (m, 4H), 6.09 (m, 1H), 6.80-6.87 (m, 1H), 7.25 (m, 10H),7.65 (m, 1H).

ESI-MS (M+H⁺)=707.

EXAMPLE 99 Preparation of Compound 99

Compound 99 was prepared by the procedures described follows:

8 ml of a 1 N LiOH aqueous solution at 0° C. was added to Intermediate 6described in Example 1 (0.107 g, 0.243 mmol, 1 eq.) in THF (11 ml). Themixture was stirred at this temperature for 5 minutes, and then at roomtemperature for 1 hour. The reaction mixture was then partitionedbetween H₂O (10 ml) and EtOAc (10 ml). The aqueous layer was acidifiedto pH=2 with a 10% KHSO₄ aqueous solution and was extracted with EtOAc(2×10 ml). The organic layers were combined, dried over Na₂SO₄, andconcentrated under vacuum to afford a crude corresponding carboxylicacid. Under an atmosphere of nitrogen, the carboxylic acid (0.100 g,0.243 mmol, 1 eq.) was dissolved slowly in anhydrous DMF (1.2 ml, 0.2M). After cesium carbonate (0.119 g, 0.365 mmol, 1.5 eq.) and benzylbromide (0.062 g, 0.040 ml, 0.365 mmol, 1.5 eq.) were sequentially addedinto the above solution, the reaction mixture was stirred at ambienttemperature overnight under N₂. The reaction was then quenched byaddition of a 10% KHSO₄ aqueous solution (5 ml) slowly. The resultantsolution was extracted with CH₂Cl₂ (5 ml×4). The organic layers werecombined, washed with brine, dried over Na₂SO₄, and concentrated undervacuum to give a crude product. The crude product thus obtained waspurified by flash chromatography (2% MeOH in CH₂Cl₂) on silica gel toafford Intermediate 8 (94 mg, 77%) as a white solid. ¹H NMR (CDCl₃) δ0.85 (d, J=4.8 Hz, 6H), 1.19 (m, 1H), 1.32 (s, 9H), 1.38-1.71 (m, 4H),1.95-2.08 (m, 2H), 2.25-2.30 (m, 2H), 3.19-3.27 (m, 2H), 4.15 (m, 1H),4.51 (m, 1H), 5.08 (s, 2H), 5.88 (d, J=15.3 Hz, 1H), 6.57 (br s, 1H),6.79 (dd, J=15.3, 4.8 Hz, 1H), 7.24 (m, 5H), 7.55(d, J=7.5 Hz, 1H).ESI-MS (M+H⁺)=502.

A 4.0 M solution of HCl in 1,4-dioxane (1.78 ml) was added to a solutionof Intermediate 8 (0.094 g, 0.187 mmol, 1 eq.) in the same solvent (1.8ml) at 23° C. After 2 hours of stirring, the reaction mixture wasconcentrated under reduced pressure. The residue thus obtained wasdissolved in CH₂Cl₂ (15 ml). Z-Thr(t-Bu)-OH (0.058 g, 0.187 mmol, 1.0eq.), 4-methylmorpholine (0.080 ml, 0.750 mmol, 4.0 eq.), HOBt (0.038 g,0.281 mmol, 1.5 eq.), and EDC (0.054 g, 0.281 mmol, 1.5 eq.) were addedsequentially. The resultant solution was stirred overnight at 23° C. andthen the solvent was removed under vacuum. The residue was partitionedbetween a 10% KHSO₄ aqueous solution (1 ml) and CH₂Cl₂ (7 ml). Theorganic layer was dried over MgSO₄, filtered, and concentrated. Thecrude product thus obtained was purified by flash chromatography (70%EtOAc in hexanes) to afford compound 99 (0.117 g, 90%) as a white foam.¹H NMR (CDCl₃) δ 0.94 (dd, J=8.4, 6.0 Hz, 6H), 1.05 (d, J=6.3 Hz, 3H),1.25 (s, 9H), 1.46-1.80 (m, 6H), 1.99-2.06 (m, 1H), 2.38 (m, 1H),3.27-3.30 (m, 2H), 4.15 (m, 2H), 4.40 (m, 1H), 4.58 (m, 1H), 5.04-5.15(m, 4H), 5.87 (s, 2H), 5.96 (dd, J=15.9, 1.2 Hz, 1H), 6.86 (dd, J=15.6,5,4 Hz, 1H), 7.28-7.33 (m, 1H), 7.61(d, J=7.2 Hz, 1H). ESI-MS(M+H⁺)=693.

EXAMPLE 100 Preparation of Compound 100

Compound 100 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.90-096 (m, 6H), 1.02-1.04 (m, 3H), 1.24 (s, 9H),1.49-1.69(m, 9H), 1.75-1.80 (m, 7H), 1.98-2.07 (m, 1H), 2.36 (m, 2H),3.25-3.28 (m, 2H), 4.14 (m, 1H), 4.41 (m, 1H), 4.56 (m, 1H), 5.08 (s,2H), 5.14-5.19 (m, 1H), 5.85-5.90 (m, 2H), 6.73-6.80 (m, 1H), 7.33 (m,5H), 7.62 (m, 1H).

ESI-MS (M+H⁺)=671.

EXAMPLE 101 Preparation of Compound 101

Compound 101 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 1.07 (d, J=6.3 Hz, 3H), 1.28 (s, 9H), 1.66-1.73 (m,4H), 2.21-2.50 (m, 8H), 2.88 (m, 2H), 3.20-3.30 (m, 2H), 4.16 (q, J=6.9Hz, 2H), 4.42 (br, 1H), 4.58 (br, 1H), 5.01-5.10 (m, 3H), 5.91 (d,J=15.6 Hz, 1H), 6.82 (dd, J=15.3 Hz, 5.1 Hz, 1H), 7.2-7.34 (m, 4H), 7.60(d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=632.

EXAMPLE 102 Preparation of Compound 102

Compound 102 was prepared in a 66% yield by reacting compound 112 with

(1.5 eq.) via a Wittig reaction for 24 hours.

¹H NMR(CDCl₃) δ 0.93-0.98(m, 6H), 1.26(s, 9H), 1.66-1.73(m, 5H),2.22-2.51(m, 4H), 3.19-3.30(m, 2H), 4.26(t, J=6.9 Hz, 2H), 4.44(br, 1H),4.57(br, 1H), 5.12(s, 2H), 6.82(d, J=5.1 Hz, 1H), 7.22-7.34(m, 4H),7.60(d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=629.

EXAMPLE 103 Preparation of Compound 103

Compound 103 was prepared in a manner similar to that described inExample 1 in a 63% yield.

¹H NMR(CDCl₃) δ 0.94-0.98 (m, 6H), 1.06 (d, 3H, J=5.7 Hz), 1.27 (s, 9H),1.53-2.10 (m, 6H), 2.38-2.43 (m, 2H), 3.28-3.30 (m, 2H), 3.72 (s, 3H),4.16 (br, 2H), 4.48 (m, 1H), 4.59 (m, 1H), 5.11 (q, 2H, J=6.6 Hz), 5.93(d, 2H, J=15.9 Hz), 6.12 (br, 1H), 6.84 (dd, 1H, J=15.6 Hz, 5.1 Hz),7.35-7.39 (m, 5H), 7.65 (d, 1H, J=6.9 Hz).

ESI-MS (M+H⁺)=617.

EXAMPLE 104 Preparation of Compound 104

Compound 104 was prepared in a manner similar to that described inExample 1 in a 35% yield.

¹H NMR(CDCl₃) δ 0.93-0.98 (m, 12H), 1.06 (d, 4H, J=5.7 Hz), 1.27 (s,9H), 1.53-2.16 (m, 7H), 2.39-2.43 (m, 2H), 3.28-3.34 (m, 2H), 3.90 (d,2H, J=6.9 Hz), 4.16-4.18 (m, 2H), 4.47-4.49 (m, 1H), 4.60 (br, 1H),5.11(q, 2H, J=6.9 Hz), 5.89 (d, 1H, J=5.4 Hz), 5.94 (d, 1H, J=15.6 Hz),6.08 (s, 1H), 6.83 (dd, 1H, J=15.6 Hz, 5.1 Hz 7.40 (m, 5H), 7.63 (d, 1H,J=7.5 Hz).

ESI-MS (M+H⁺)=659.

EXAMPLE 105 Preparation of Compound 105

Compound 105 was prepared in a manner similar to that described inExample 1 in a 79% yield.

¹H NMR (CDCl₃) δ 0.93-0.98 (m, 6H), 1.05 (d, 3H, J=5.4 Hz), 1.26 (s,9H), 1.53-2.11 (m, 7H), 2.37 (br, 2H), 3.28-3.33 (m, 2H), 4.16 (br, 2H),4.50-4.52 (m, 2H), 4.62 (d, 2H, J=5.7 Hz), 5.10 (q, 2H, J=6.6 Hz), 5.23(d, 1H, J=10.2 Hz), 5.31 (d, 1H, J=17.4 Hz), 5.85-5.98 (m, 3H), 6.86(dd, 1H, J=15.6 Hz, 5.4 Hz), 7.35-7.41 (m, 5H), 7.69-7.74 (m, 1H).

ESI-MS (M+H⁺)=643.

EXAMPLE 106 Preparation of Compound 106

Compound 106 was prepared in a manner similar to that described inExample 1 in a 92% yield.

¹H NMR (CDCl₃) δ 0.92-0.97 (m, 6H), 1.1 (d, 3H, J=6 Hz), 1.28 (s, 9H),1.52-2.19 (m, 6H), 2.43 (br, 2H), 3.19 (s, 3H), 3.28-3.30 (m, 2H), 3.78(s, 3H), 4.17-4.19 (m, 2H), 4.38 (br, 1H), 4.90-4.95 (m, 1H), 5.10 (q,2H, J=8.7 Hz), 5.96 (m, 2H), 7.30-7.35 (m, 5H), 7.44 (d, 1H, J=7.8 Hz).

ESI-MS (M+H⁺)=620

EXAMPLE 107 Preparation of Compound 107

Compound 107 was prepared in a 88% yield by reducing compound 103 withLiBR₄ (1.5 eq.).

¹H NMR(CDCl₃) δ 0.92-0.99(m, 6H), 1.26(s, 9H), 1.66-1.73(m, 5H),2.21-2.50(m, 2H), 3.20-3.32(m, 2H), 3.62(m, 1H), 3.75(d, J=7.5 Hz, 2H),4.42(br, 1H), 4.58(br, 1H), 5.10(s, 2H), 7.21-7.34(m, 4H), 7.61(d, J=7.5Hz, 1H).

ESI-MS (M+H⁺)=563.

EXAMPLE 108 Preparation of Compound 108

Compound 108 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=612.

EXAMPLE 109 Preparation of Compound 109

Compound 109 was prepared as follows: Dry THF (5 ml) and1-methyl-1-propenyl magnesium bromide (0.5 M in THF, 22 ml) were addedto compound 106 (0.124 g, 0.2 mmol) under N₂. The mixture was stirred atroom temperature under N₂ for 30 minutes, and then quenched by slowlyadding a 10% HCl solution until the pH value was about 7. The mixturewas then washed with brine and extracted with EtOAc (3×50 ml). Theorganic layers were combined, and dried with Na₂SO₄. The crude productwas purified by silica gel chromatography using 2% MeOH/CH₂Cl₂ as aneluant to afford compound 109 as a white solid (0.085 mg, 69%).

¹H NMR (CDCl₃) δ 0.91-0.96 (m, 6H), 1.09 (d, 3H, J=6 Hz), 1.28 (s, 9H),1.49-1.83 (m, 5H), 1.79 (s, 3H), 1.89 (d, 3H, J=6.9 Hz), 2.03-2.13 (m,1H), 2.30-2.41 (m, 1H), 2.48 (m, 1H), 3.25-3.30 (m, 2H), 4.17-4.19 (m,2H), 4.38-4.39 (m, 1H), 5.11 (q, 2H, J=7.8 Hz), 5.33-5.38 (m, 1H),5.92-5.97 (m, 2H), 6.85 (q, 1H, J=6.3 Hz), 7.13-7.15 (m, 1H), 7.30-7.35(m, 5H), 7.42 (d, 1H, J=7.8 Hz).

ESI-MS (M+H¹)=615.

EXAMPLE 110 Preparation of Compound 110

Compound 110 was prepared in a manner similar to that of compound 109 ina 44% yield.

¹H NMR (CDCl₃) δ 0.95 (m, 6H), 1.09 (d, 3H, J=6.6 Hz), 1.27 (s, 9H),1.52-1.85 (m, 5H), 2.05-2.14 (m, 1H), 2.38-2.42 (m, 2H), 3.28-3.33 (m,2H), 4.17-4.19 (m, 2H), 4.40-4.42 (m, 1H), 4.79-4.84 (m, 1H), 5.11 (q,2H, J=7.8 Hz), 5.84-5.92 (m, 3H), 6.36-6.56 (m, 2H), 7.31-7.35 (m, 5H),7.42 (d, 1H, J=7.8 Hz), 7.61 (d, 1H, J=7.2 Hz).

ESI-MS (M+H⁺)=587.

EXAMPLE 111 Preparation of Compound 111

Compound 111 was prepared in a manner similar to that of compound 109.

¹H NMR (CDCl₃) δ 0.96 (m, 6H), 1.08 (d, 3H, J=5.7 Hz), 1.27 (s, 9H),1.54-1.78 (m, 5H), 2.03-2.07 (m, 1H), 2.25 (s, 3H), 2.40 (m, 2H),3.28-3.32 (m, 2H), 4.16-4.19 (m, 2H), 4.60-4.61 (m, 1H), 5.11 (q, 2H,J=6.3 Hz), 5.88 (d, 1H, J=4.8 Hz), 6.02 (s, 1H), 6.16 (d, 1H, J=16.2Hz), 6.66 (dd, 1H, J=15.9 Hz, 5.1 Hz), 7.35 (m, 5H), 7.73 (d, 1H, J=7.5Hz).

ESI-MS (M+H⁺)=601.

EXAMPLE 112 Preparation of Compound 112

Compound 112 was prepared in a 99% yield by reacting compound 107 withSO₃Py (2.5 eq.) via a Swern oxidation reaction for 1 hour.

¹H NMR (CDCl₃) δ 0.92-0.98 (m, 6H), 1.26 (s, 9H), 1.66-1.73 (m, 5H),2.21-2.50 (m, 2H), 3.20-3.32 (m, 2H), 4.42 (br, 2H), 4.59 (br, 1H), 5.11(s, 2H), 7.21-7.34 (m, 4H), 7.61 (d, J=7.5 Hz, 1H), 9.82 (s, 1H).

ESI-MS (M+H⁺)=561.

EXAMPLE 113 Preparation of Compound 113

Compound 113 was prepared in a 68% yield in a manner similar to that ofcompound 89 using compound 102 as a starting material.

¹H NMR (CDCl₃) δ 0.94-0.99 (m, 6H), 1.25 (s, 9H), 1.66-1.73 (m, 5H),2.22-2.51 (m, 4H), 3.19-3.30 (m, 2H), 4.26 (t, J=6.9 Hz, 2H), 4.44 (br,1H), 4.57 (br, 1H), 5.12 (s, 2H), 6.82 (d, J=5.1 Hz, 1H), 7.22-7.34 (m,4H), 7.61 (d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=657.

EXAMPLE 114 Preparation of Compound 114

Methylsulfoxide and triethylamine were added to a solution of compound107. The solution was cooled to 0-5° C. with an ice-water bath, followedby addition of sulfur trioxide-pyridine complex. The reaction mixturewas stirred at that temperature for 1 hour. After adding

and stirring the reaction mixture at ambient temperature for another 3hours, the reaction mixture was quenched by addition of saturated brineand subsequently extracted with ethyl acetate. The organic layers werecombined, dried over MgSO₄, filtered, and concentrated to afford a darkred oil. The oil was purified though a chromatography (50% EA in hexane)to afford compound 114 as a white solid.

ESI-MS (M+H⁺)=627.

EXAMPLE 115 Preparation of Compound 115

Compound 115 was prepared in a manner similar to that described inExample 1 in a 65% yield.

¹H NMR (CDCl₃) δ 0.90-095 (m, 6H), 1.03-1.05 (m, 4H), 1.23 (s, 9H),1.44-1.88 (m, 5H), 1.97 (m, 2H), 2.37 (m, 2H), 3.24-3.32 (m, 2H), 3.69(s, 3H), 4.14 (m, 1H), 4.40-4.52 (m, 2H), 5.07 (s, 2H), 5.88-5.91 (m,1H), 6.23 (m, 1H), 7.33 (m, 5H), 7.45 (m, 1H), 7.77 (m, 1H).

ESI-MS (M+H⁺)=591.

EXAMPLE 116 Preparation of Compound 116

Compound 116 was prepared in a 77% yield in a manner similar to that ofcompound 109 using compound 106 as a starting material.

¹H NMR (CDCl₃) δ 0.94-0.99 (m, 6H), 1.09 (d, 3H, J=6 Hz), 1.27 (s, 9H),1.53-1.84 (m, 5H), 2.02-2.12 (m, 1H), 2.20 (s, 3H), 2.32-2.43 (m, 2H),3.24-3.35 (m, 2H), 5.11 (q, 2H, J=6 Hz), 5.90 (d, 1H, J=3 Hz), 5.98 (m,1H), 7.32-7.36 (m, 5H), 7.42 (d, 1H, J=6 Hz), 7.83 (d, 1H, J=9 Hz).

ESI-MS (M+H⁺)=575.

EXAMPLE 117 Preparation of Compound 117

Compound 117 was prepared by the procedures described below:

Triethylamine (0.25 ml, 1.757 mmol, 4.53 eq.) was added to a solution ofIntermediate 4 described in Example 1 (0.100 g, 0.387 mmol, 1 eq.) inDMSO (1.1 ml). The solution was cooled to 0° C. with an ice bath,followed by addition of sulfur trioxide-pyridine complex (0.568 g, 1.742mmol, 4.5 eq.). The ice bath was removed after the addition and thereaction mixture was stirred at room temperature for 1 hour.1-Acetyl-3-(triphenyl-15-phosphanylidene)-pyrrolidin-2-one (0.600 g,1.548 mmol, 4 eq.) was then added into the mixture. After stirring themixture at room temperature overnight, the reaction was quenched bysaturated brine (7 ml) and then extracted with ethyl acetate (3×10 ml).The organic layers were combined, washed with saturated brine (3×15 ml),dried over MgSO₄, filtered, and concentrated to afford a dark red oil.The oil was purified through a column chromatography (2% MeOH in CH₂Cl₂)to afford Intermediate 9 as a white solid (75 mg, 53%). ESI-MS(M+H⁺)=366.

Intermediate 9 (0.446 g, 1.220 mmol, 1 eq.) was dissolved in a solutionof HCl in 1,4-dioxane (4.0 M, 10 ml) was added to. The solution wasstirred at room temperature for 30 minutes and 1,4-dioxane was removedunder vacuum. CH₂Cl₂ (1.5 ml) was then added to the residue, followed byaddition of N-methylmorpholine (0.540 ml, 4.880 mmol, 4 eq.),Z-Thr(t-Bu)-Leu-OH (0.515 g, 1.220 mmol, 1.0 eq.), HOBt (0.250 g, 1.830mmol, 1.5 eq.), and EDC (0.351 g, 1.830 mmol, 1.5 eq.). The reactionmixture was stirred at room temperature overnight and then concentratedunder vacuum. The residue was partitioned between a 10% KHSO₄ (6.5 ml)aqueous solution and CH₂Cl₂ (45 ml). The organic layer was collected,dried over MgSO₄, filtered, and concentrated. The crude product waspurified by flash chromatography (2% MeOH in CH₂Cl₂) to afford compound117 (0.572 g, 70%) as a white solid. ¹H NMR (CDCl₃) δ 0.88-0.98 (m, 6H),1.07 (d, J=6.0 Hz, 3H), 1.25(s, 9H), 1.48-1.62 (m, 3H), 1.74-1.90 (m,3H), 2.06-2.16 (m, 3H), 2.32-2.47 (m, 3H), 2.54 (s, 3H), 2.71 (m, 1H),3.03 (m, 1H), 3.27-3.30 (m, 3.77 (dd, J=7.5, 7.5 Hz, 2H), 4.14-4.18 (m,2H), 4.53 (m, 1H), 4.60 (m, 1H), 5.00-5.18 (m, 2H), 5.87 (d, J=5.1 Hz,1H), 6.02 (br s, 1H), 6.43 (d, J=9.0 Hz, 1H), 7.27-7.34 (m, 5H), 7.76(d,J=6.9 Hz, 1H). ESI-MS (M+H⁺)=670.

EXAMPLE 118 Preparation of Compound 118

Compound 118 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.9 (m, 6H), 1.16 (s, 9H), 1.49-2.17 (m, 8H), 2.38-2.41(m, 2H), 3.32-3.35 (m, 2H), 3.58-3.70 (m, 2H), 4.27-4.28 (m, 1H), 4.37(t, 3H, J=7.5 Hz), 4.57 (br, 1H), 5.10 (q, 2H, J=5.7 Hz), 6.30 (s, 1H),6.49-6.52 (m, 2H), 6.63-6.65 (m, 1H), 7.16 (d, 1H, J=8.4 Hz), 7.34 (br,5H), 8.17 (d, 1H, J=6.3 Hz).

ESI-MS (M+H⁺)=642.

EXAMPLE 119 Preparation of Compound 119

Compound 119 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=657.

EXAMPLE 120 Preparation of Compound 120

Compound 120 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.85-0.90 (m, 6H), 1.39 (s, 9H), 1.56-1.81 (m, 5H),2.01-2.09 (m, 4H), 2.41 (m, 1H), 3.16 (s, 3H), 3.28-3.30 (m, 2H),3.44-3.48 (m, 2H), 3.78 (s, 3H), 4.30-4.40 (m, 2H), 4.83-4.88 (m, 1H),5.09 (s, 2H), 5.64 (br s, 1H), 6.32 (br s, 1H), 7.26-7.33 (m, 5H),7.77-7.79 (m, 1H).

ESI-MS (M+H⁺)=645.

EXAMPLE 121 Preparation of Compound 121

Compound 121 was prepared in a manner similar to that described inExample 1 in a 10% yield.

¹H NMR (CDCl₃) δ 0.87 (m, 6H), 1.26 (s, 9H), 1.53-1.76 (m, 5H), 1.99 (m,6H), 2.38 (m, 2H), 2.88 (m, 1H), 3.14-3.48 (m, 4H), 4.14 (m, 1H), 4.35(m, 2H), 4.56 (m, 1H), 5.07 (s, 2H), 6.40-6.46 (m, 1H), 7.04 (m, 1H),7.31 (m, 5H), 8.08 (m, 1H).

ESI-MS (M+H⁺)=657.

EXAMPLE 122 Preparation of Compound 122

Compound 122 was prepared in a manner similar to that of compound 109 ina 60% yield.

¹H NMR (CDCl₃) δ 0.93 (m, 6H), 1.16 (s, 9H), 1.45-1.82 (m, 5H),2.00-2.09 (m, 1H), 2.45 (s, 3H), 2.37-2.46 (m, 2H), 3.31-3.34 (m, 2H),3.64-3.68 (m, 2H), 4.27-4.29 (m, 1H), 4.44-4.50 (m, 1H), 4.59-4.60 (m,1H), 5.10 (q, 2H, J=5.1 Hz), 6.10 (s, 1H), 6.17 (d, 1H, J=1.2 Hz), 6.48(br, 1H), 6.68 (dd, 2H, J=15.6 Hz, 5.7 Hz), 7.13 (d, 1H, J=8.1 Hz), 7.34(br, 5H), 8.01 (d, 1H, J=6.9 Hz).

ESI-MS (M+H⁺)=614.

EXAMPLE 123 Preparation of Compound 123

Compound 123 was prepared in a manner similar to that of compound 109 ina 32% yield.

¹H NMR (CDCl₃) δ 0.92-0.98 (m, 6H), 1.06-1.11 (m, 6H), 1.26 (s, 9H),1.53-2.10 (m, 6H), 2.39 (m, 2H), 2.56 (q, 2H, J=7.2 Hz), 3.28-3.31 (m,2H), 4.15-4.18 (m, 2H), 4.44-4.45 (m, 1H), 4.58 (m, 1H), 5.11 (q, 2H,J=6.3 Hz), 5.89 (d, 1H, J=4.8 Hz), 6.04 (s, 1H), 6.19 (d, 1H, J=15.3Hz), 6.69 (dd, 1H, J=15.9 Hz, 5.4 Hz), 7.35 (m, 5H), 7.71 (d, 1H, J=7.5Hz).

ESI-MS (M+H⁺)=615.

EXAMPLE 124 Preparation of Compound 124

Compound 124 was prepared in a manner similar to that described inExample 1.

ESI-MS (M+H⁺)=615.

EXAMPLE 125 Preparation of Compound 125

Compound 125 was prepared in a manner similar to that of compound 109 ina 55% yield.

¹H NMR (CDCl₃) δ 0.91(q, 6H, J=6 Hz), 1.41 (s, 9H), 1.55-1.81 (m, 5H),2.10 (m, 1H), 2.23 (s, 3H), 2.36-2.40 (m, 2H), 2.78 (m, 2H), 3.30-3.33(m, 2H), 4.46-4.52 (m, 1H), 4.56-4.59 (m, 2H), 5.11 (q, 2H, J=6.6 Hz),6.01 (d, 1H, J=8.4 Hz), 6.15 (d, 1H, J=15.6 Hz), 6.30 (s, 1H), 6.65 (dd,1H, J=16.2 Hz, 5.4 Hz), 7.17 (d, 1H, J=8.4 Hz), 7.34 (m, 5H), 7.89 (d,1H, J=7.8 Hz).

ESI-MS (M+Na⁺)=637.

EXAMPLE 126 Preparation of Compound 126

Compound 126 was prepared in a manner similar to that of compound 109 inan 82% yield.

¹H NMR (CDCl₃) δ 0.86-0.97 (m, 6H), 1.14-1.38 (m, 6H), 1.49-1.66 (m,1H), 1.98-2.08 (m, 2H), 2.23 (s, 3H), 2.34-2.45 (m, 2H), 3.29-3.33 (m,2H), 3.62-3.68 (m, 2H), 4.26 (dd, J=9.9, 5.4 Hz, 1H), 4.43 (m, 1H), 4.59(m, 1H), 5.04-5.14 (m, 2H), 6.08-6.18 (m, 2H), 6.37 (br s, 1H),6.64-6.71 (dd, J=16.2, 5.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.28-7.34(m, 5H), 7.98 (d, J=6.9 Hz, 1H).

ESI-MS (M+H⁺)=640.

EXAMPLE 127 Preparation of Compound 127

Compound 127 was prepared in a manner similar to that of compound 109 ina 78% yield.

¹H NMR (CDCl₃) δ 0.85-0.93 (m, 6H), 0.98 (s, 9H), 1.48-1.64 (m, 4H),1.75-1.85 (m, 1H), 1.91 (m, 1H), 1.98-2.08 (m, 1H), 2.03 (s, 3H), 2.23(s, 3H), 2.37-2.46 (m, 2H), 3.29-3.36 (m, 2H), 3.54-3.72 (m, 2H), 4.24(m, 1H), 4.44 (m, 1H), 4.58 (m, 1H), 5.02-5.12 (m, 2H), 6.15 (d, J=15.9Hz, 1H), 6.55-6.78 (m, 3H), 7.28-7.31 (m, 5H), 7.97 (d, J=6.6 Hz, 1H).

ESI-MS (M+H⁺)=628.

EXAMPLE 128 Preparation of Compound 128

Compound 128 was prepared in a manner similar to that of compound 109 ina 25% yield.

¹H NMR (CDCl₃) δ 0.89 (m, 6H), 1.39 (s, 9H), 1.53-2.14 (m, 7H), 2.22 (s,3H), 2.39 (m, 2H), 3.29-3.30 (m, 2H), 3.46 (m, 2H), 4.21 (m, 2H), 4.43(m, 1H), 4.58 (m, 1H), 5.09 (s, 2H), 6.18 (m, 2H), 6.46 (m, 1H),6.62-6.69 (m, 1H), 7.32 (m, 5H), 7.93 (m, 1H),

ESI-MS (M+H⁺)=630.

EXAMPLE 129 Preparation of Compound 129

Compound 129 was prepared in a manner similar to that of compound 112 ina 38% yield.

¹H NMR(CDCl₃) δ 0.92-0.98(m, 6H), 1.27(s, 9H), 1.65-1.72(m, 5H),2.22-2.51(m, 2H), 3.20-3.32(m, 2H), 4.43(br, 2H), 4.59(br, 1H), 5.12(s,2H), 7.21-7.35 (m, 4H), 7.60(d, J=7.5 Hz, 1H), 9.82(s, 1H)

ESI-MS (M+H⁺)=604.3.

EXAMPLE 130 Preparation of Compound 130

Compound 130 was prepared in a manner similar to that of compound 131.

¹H NMR(CDCl₃) δ 0.93-0.98(m, 6H), 1.26(s, 9H), 1.65-1.72(m, 5H),2.22-2.51(m, 2H), 3.20-3.32(m, 2H), 3.58(d, J=7.2 Hz, 2H), 3.86(m, 1H),4.44(br, 2H), 5.12(s, 2H), 7.21-7.35(m, 4H), 7.60(d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=624.3.

EXAMPLE 131 Preparation of Compound 131

Compound 131 was prepared in a 51% yield by reacting compound 107 withthionyl chloride in CH₂Cl₂ at room temperature for 6 hours.

¹H NMR(CDCl₃) δ 0.93-0.98(m, 6H), 1.28(s, 9H), 1.65-1.72(m, 5H),2.22-2.50(m, 2H), 3.20-3.32(m, 2H), 3.58(d, J=7.2 Hz, 2H), 3.86(m, 1H),4.42(br, 2H), 5.11(s, 2H), 7.21-7.35(m, 4H), 7.60(d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=581.3.

EXAMPLE 132 Preparation of Compound 132

1-(2,2,2-Trifluoro-1-methyl-ethylidene)-pyrrolidinium (1.5 eq.) wasprepared from methyltrifluoromethylketone and pyrrolidine at 0° C.Compound 112 (1.0 eq.) was then added in situ to afford compound 132 ina 43% yield.

¹H NMR(CDCl₃) δ 0.94-0.98(m, 6H), 1.27(s, 9H), 1.66-1.73(m, 5H),2.25-2.53(m, 2H), 3.22-3.31(m, 2H), 4.44(m, 1H), 4.63(m, 1H), 5.10(s,2H), 6.21(d, J=18.1 Hz, 1H), 6.98(dd, J=18.1 Hz, 5.1 Hz, 1H),7.22-7.35(m, 4H), 7.62(d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=655.

EXAMPLE 133 Preparation of Compound 133

Compound 133 was prepared in a manner similar to that of compound 112 ina 35% yield.

¹H NMR(CDCl₃) δ 0.89-0.95 (m, 6H), 1.42 (s, 9H), 1.55-2.06 (m, 6H),2.37-2.47 (m, 2H), 2.64-2.94 (m, 2H), 3.32-3.34 (m, 2H), 4.45-4.58 (m,3H), 5.12 (s, 2H), 6.00-6.16 (m, 2H), 7.35 (m, 5H), 9.49 (d, 1H, J=16.5Hz).

ESI-MS (M+H¹)=575.

EXAMPLE 134 Preparation of Compound 134

Compound 134 was prepared in a manner similar to that of compound 112 ina 35% yield.

¹H NMR (CDCl₃) δ 0.87-1.26 (m, 20H), 1.69-1.97 (m, 14H), 2.43 (m, 1H),3.64 (m, 1H), 4.18 (m, 2H), 4.40 (m, 1H), 5.09 (s, 2H), 5.90 (m, 1H),7.36 (m, 5H), 9.50 (s, 1H).

ESI-MS (M+H⁺)=601.

EXAMPLE 135 Preparation of Compound 135

Compound 135 was prepared in a manner similar to that of compound 109.

¹H NMR (CDCl₃) δ 0.93 (q, 6H, J=5.7 Hz), 1.03-1.08 (m, 9H), 1.23 (s,9H), 1.49-1.83 (m, 5H), 2.00-2.03 (m, 1H), 2.36 (m, 2H), 2.70-2.79 (m,1H), 3.26-3.29 (m, 2H), 4.13-4.17 (m, 2H), 4.43-4.44 (m, 1H), 4.58-4.60(m, 1H), 5.09 (q, 2H, J=5.4 Hz), 5.86 (d, 1H, J=5.1 Hz), 6.01 (s, 1H),6.26 (d, 1H, J=15.6 Hz), 6.71 (dd, 1H, J=15.6 Hz, 5.4 Hz), 7.30-7.34 (m,5H), 7.60 (d, 1H, J=7.8 Hz).

ESI-MS (M+H⁺)=629.

EXAMPLE 136 Preparation of Compound 136

Compound 136 was prepared in a manner similar to that of compound 109 ina 36% yield.

¹H NMR (CDCl₃) δ 0.93 (q, 6H, J=5.7 Hz), 1.06 (d, 3H, J=6.3 Hz), 1.23(s, 9H), 1.44-1.77 (m, 5H), 1.99-2.07 (m, 1H), 2.39 (m, 2H), 3.27-3.30(m, 2H), 4.15-4.18 (m, 2H), 4.39-4.41 (m, 1H), 4.62 (m, 1H), 5.10 (q,2H, J=6 Hz), 5.82-5.87 (m, 3H), 6.28 (d, 1H, J=16.5 Hz). 6.47-6.56 (m,2H), 6.77 (dd, 1H, J=15.3 Hz, 4.8 Hz), 7.29-7.34 (m, 5H), 7.66 (d, 1H,J=7.5 Hz).

ESI-MS (M+Na⁺)=635.

EXAMPLE 137 Preparation of Compound 137

Compound 137 was prepared in a manner similar to that of compound 109.

¹H NMR (CDCl₃) δ 0.94-0.97 (m, 6H), 1.08 (d, 3H, J=6.3 Hz), 1.27 (s,9H), 1.52-1.86 (m, 11H), 2.02-2.09 (m, 1H), 2.40 (m, 2H), 3.29-3.32 (m,2H), 4.16 (m, 2H), 4.41 (m, 1H), 4.62 (m, 1H), 5.11 (q, 2H, J=5.4 Hz),5.81-5.89 (m, 2H), 6.61-6.79 (m, 3H), 7.35 (m, 5H), 7.53 (d, 1H, J=7.2Hz).

ESI-MS (M+H⁺)=641.

EXAMPLE 138 Preparation of Compound 138

Compound 138 was prepared in a manner similar to that of compound 109 ina 26% yield.

¹H NMR (CDCl₃) δ 0.87-1.26 (m, 20H), 1.52-1.72 (m, 9H), 2.21-2.22 (m,3H), 2.38 (m, 2H), 3.27-3.30 (m, 2H), 4.15 (m, 2H), 4.39 (m, 1H), 4.58(m, 1H), 5.09 (s, 2H), 5.86 (m, 2H), 6.12-6.22 (m, 1H), 6.61-6.68 (m,1H), 7.33 (m, 5H), 7.65 (m, 1H).

ESI-MS (M+H⁺)=641.

EXAMPLE 139 Preparation of Compound 139

Compound 139 was prepared in a manner similar to that of compound 109 ina 28% yield.

¹H NMR (CDCl₃) δ 0.62-0.70 (m, 8H), 0.79-0.80 (m, 6H), 0.99 (s, 9H),1.26-1.85 (m, 6H), 2.12 (m, 2H), 3.00-3.03 (m, 2H), 4.16 (m, 2H), 4.46(m, 1H), 4.62 (m, 1H), 5.06-5.16 (m, 2H), 5.89 (s, 1H), 6.10 (s, 1H),6.32 (d, 1H, J=15.6 Hz), 6.74 (dd, 1H, J=15.6 Hz, 5.1 Hz), 7.36 (m, 5H),7.69 (m, 1H).

ESI-MS (M+Na⁺)=649.

EXAMPLE 140 Preparation of Compound 140

Compound 140 was prepared in a manner similar to that of compound 109 ina 37% yield.

¹H NMR (CDCl₃) δ 0.93 (q, 6H, J=6 Hz), 1.04 (d, 3H, J=6 Hz), 1.23 (s,9H), 1.49-1.83 (m, 5H), 1.89 (s, 3H), 1.99-2.09 (m, 1H), 2.37-2.42 (m,2H), 3.27 (d, 2H, J=9 Hz), 4.12-4.17 (m, 2H), 4.39-4.44 (m, 1H),4.58-4.63 (m, 1H), 5.09 (q, 2H, J=5.4 Hz), 5.78 (s, 1H), 5.86 (d, 1H,J=5.1 Hz), 5.94 (s, 1H), 6.00 (m, 2H), 6.72-6.74 (m, 2H), 7.30-7.34 (m,5H), 7.63 (d, 1H, J=7.5 Hz).

ESI-MS (M+H⁺)=627.

EXAMPLE 141 Preparation of Compound 141

Compound 141 was prepared in a manner similar to that of compound 109 ina 82% yield.

¹H NMR (CDCl₃) δ 0.86-1.02 (m, 15H), 1.09-1.31 (m, 9H), 1.45-1.85 (m,6H), 2.16-2.24 (m, 2H), 2.22 (s, 3H), 2.30-2.41 (m, 2H), 3.22-3.32 (m,2H), 4.10 (dd, J=5.4, 5.4 Hz, 1H), 4.23 (ddd, J=8.1, 6.0, 2.4 Hz, 1H),4.46 (m, 1H), 4.63(m, 1H), 4.99-5.14 (m, 2H), 5.38 (d, J=5.1 Hz, 1H),5.88 (br s, 1H), 6.69 (dd, J=15.9, 5.1 Hz, 1H), 7.14 (d, J=6.0 Hz, 1H),7.32-7.37 (m, 5H), 7.43 (m, 1H).

ESI-MS (M+H⁺)=700.

EXAMPLE 142 Preparation of Compound 142

Compound 142 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.73-0.87 (m, 5H), 1.03 (d, J=6.0 Hz, 3H), 1.05 (d,J=6.0 Hz, 3H), 1.14 (s, 3H), 1.22-1.28 (m, 18H), 1.77-1.82 (m, 1H),2.04-2.12 (m, 1H), 2.32-2.48 (m, 2H), 3.28-3.32 (m, 2H), 4.13-4.19 (m,6H), 4.32-4.35 (m, 1H), 4.69-4.78 (m, 1H), 5.05-5.16 (m, 2H), 5.50 (brs, 1H), 5.89 (d, J=18, 1H), 6.13 (d, J=16 Hz, 1H), 6.85 (dd, J=16.0, 5.5Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 7.34 (m, 5H), 7.63 (d, J=6.0 Hz, 1H).

ESI-MS (M+Na⁺)=675.

EXAMPLE 143 Preparation of Compound 143

Compound 143 was prepared in a manner similar to that of compound 109 ina 82% yield.

¹H NMR (CDCl₃) δ 0.84-0.94 (m, 6H), 1.10 (d, J=6.0 Hz, 3H), 1.15-1.24(m, 5H), 1.49-1.79 (m, 10H), 2.03 (m, 1H), 2.22 (s, 3H), 2.38 (m, 2H),3.28-3.31 (m, 2H), 3.39 (m, 1H), 4.15 (m, 2H), 4.45-4.58 (m, 2H), 5.09(s, 2H), 5.75 (d, J=5.7 Hz, 1H), 5.90 (br s, 1H), 6.15 (d, J=15.9 Hz,1H), 6.65 (dd, J=15.9, 5.4 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.30-7.34(m, 5H), 7.75 (d, J=7.5 Hz, 1H).

ESI-MS (M+H⁺)=627.

EXAMPLE 144 Preparation of Compound 144

Compound 144 was prepared in a manner similar to that described inExample 1.

¹H NMR (CDCl₃) δ 0.86-1.27 (m, 17H), 1.47-1.76 (m, 14H), 1.97-2.05 (m,1H), 2.38 (br s, 2H), 3.28 (m, 2H), 4.15 (m, 4H), 4.38 (m, 1H), 4.58 (m,1H), 5.04-5.14 (m, 2H), 5.79-5.93 (m, 3H), 6.80 (dd, 1H, J=15.9 Hz, 5.7Hz), 7.34 (m, 5H), 7.60 (m, 1H),

ESI-MS (M+H⁺)=671.

EXAMPLE 145 Preparation of Compound 145

Compound 145 was prepared in a manner similar to that of compound 109 ina 25% yield.

¹H NMR (CDCl₃) δ 0.73-0.87 (m, 5H), 0.95 (d, J=6.0 Hz, 3H), 1.14 (s,9H), 1.47-1.69 (m, 13H), 1.90-1.99 (m, 3H), 2.00-2.36 (m, 3H), 3.17 (m,2H), 4.05 (m, 2H), 4.30 (m, 1H), 4.51 (m, 1H), 4.94-5.04 (m, 2H),5.77-5.81 (m, 2H), 6.21 (d, J=16.0 Hz 1H), 6.62 (dd, J=16.0, 5.5 Hz,1H), 7.34 (m, 5H), 7.52 (d, J=7.8 Hz, 1H).

ESI-MS (M+Na⁺)=667.

EXAMPLE 146 in vitro Assay

A fusion protein, prepared by fusing a severe acute respiratory syndrome3CL protease to E. coli maltose-binding protein (MBP), was expressed inE coli BL21 (DE3) pLys S cells (Novagen, Oakland, Calif.). Fusionprotein thus obtained was purified by amylose-affinity chromatographyand cleaved with factor Xa to release the severe acute respiratorysyndrome 3CL protease. Subsequently, the recombinant protease waspurified to homogeneity using phenyl Sepharose CL-4B column (Pharmacia,Uppsala, Sweden) and was concentrated to form a 25 μM solution.

The enzymatic activity of severe acute respiratory syndrome 3CL protease(75 nM) was determined by incubation with a solution containing 15 μM ofa substrate peptide (SITSAVLQSGFRKMA, SEQ ID No: 1) at 25° C. for 30minutes in a medium containing 20 mM Tris-HCl (pH 7.5), 200 mM NaCl, 1mM EDTA, 1 mM dithiothretol, and 1 mg/mL bovine serum albumin. Thereaction was terminated by adding an equal volume of 0.2%trifluoroacetic acid. The reaction mixture was analyzed by reverse-phaseHPLC using a C18 column. Cleaved products were resolved using a 5-95%linear gradient of acetonitrile in 0.9% trifluoroacetic acid.Quantification of peak areas was used to determine the extent ofsubstrate conversion.

Compounds 1-145 were tested for their efficacy in inhibiting severeacute respiratory syndrome 3CL protease. Specifically, a test compoundand the severe acute respiratory syndrome 3CL protease werepre-incubated at 25° C. for 20 minutes before they were incubated withthe substrate peptide. Unexpectedly, 77 compounds show IC₅₀ values lowerthan 1 μM, 32 compounds show IC₅₀ values between 1 μM and 10 μM, and 12compounds show IC₅₀ values above 10 μM.

OTHER EMBODIMENTS

All of the features disclosed in this specification may be combined inany combination. Each feature disclosed in this specification may bereplaced by an alternative feature serving the same, equivalent, orsimilar purpose. Thus, unless expressly stated otherwise, each featuredisclosed is only an example of a generic series of equivalent orsimilar features.

From the above description, one skilled in the art can easily ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the scope of thefollowing claims.

1. A compound of formula (I):

wherein X is N(R_(a1)); in which R_(a1) is H or C₁-C₁₅ alkyl; R₁ isCO₂R_(b2); in which R_(b2) is H, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, aryl, heteroaryl, or C₁-C₁₅ alkyl optionallysubstituted with halogen, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,OR_(b5), CO₂R_(b5), or S(O)₂R_(b5); R_(b5) being H, C₁-C₁₅ alkyl,heteroaryl, or aryl; each of R₂ and R₃, independently, is H, C₁-C₁₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl,OR_(c1), SR_(c1), or NR_(c1)R_(c2); in which each of R_(c1) and R_(c2),independently, is H, C₁-C₆ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; each of R₄ and R₅, independently,is H, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; one of R₆ and R₇ is C₁-C₁₅ alkyl substituted with2-oxo-3-pyrrolidinyl; and the other of R₆ and R₇ is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; R₈ isH, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, aryl, OR_(d1), or SR_(d1); in which R_(d1) is H and C₁-C₁₅alkyl; and one of R₉ and R₁₀ is C(O)R_(e1); the other of R₉ and R₁₀ isH, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, aryl, C(O)R_(e1), CO₂R_(e1), C(O)NR_(e1)R_(e2),C(O)—N(R_(e1))—OR_(e2), C(S)R_(e1), C(S)NR_(e1)R_(e2), CN, NO₂,S(O)R_(e1), SO₂R_(e1), S(O)NR_(e1)R_(e2), S(O)—N(R_(e1))—OR_(e2),S(O)₂NR_(e1)R_(e2),SO₃R_(e1), PO(OR_(e1)) (OR_(e2)), PO(R_(e1))(R_(e2)),PO(NR_(e1)R_(e2))(OR_(e3)), PO(NR_(e1)R_(e2))(NR_(e3)R_(e4)),C(O)—N(R_(e1))—NR_(e2)R_(e3), or C(S)—N(R_(e1))— NR_(e2)R_(e3); in whicheach of R_(e1), R_(e2), R_(e3), and R_(e4), independently, is H, C₁-C₁₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl;or any two of R_(e1), R_(e2), R_(e3), and R_(e4), together with the atomor atoms to which they are bonded, are C₃-C₂₀ heterocycloalkyl.
 2. Thecompound of claim 1, wherein X is N(R_(a1)); R₁ is CO₂R_(b2), in whichR_(b2) is aryl or C₁-C₁₅ alkyl optionally substituted with halogen,OR_(b5), or CO₂R_(b5); each of R₂ and R₃, independently, is H or C₁-C₁₅alkyl optionally substituted with OR_(c1), C(O)—NR_(c1)R_(c2),NR_(c1)R_(c2), N(R_(e1))—CO₂R_(c2), N(R)_(c1))—SO₂R_(c2), orO—SO₂-R_(c1); each of R₄ and R₅, independently, is H or C₁-C₁₅ alkyl;one of R₆ and R₇ is C₁-C₁₅ alkyl substituted with 2-oxo-3-pyrrolidinyl,and the other of R₆ and R₇ is H; and R₈ is H.
 3. The compound of claim2, wherein one of R₆ and R₇ is


4. The compound of claim 3, wherein one of R₄ and R₅ is H or C₁-C₁₅alkyl optionally substituted with aryl.
 5. A pharmaceutical compositioncomprising a compound of claim 1 and a pharmaceutically acceptablecarrier.
 6. A compound of formula (I):

wherein X is N(R_(a1)); in which R_(a1) is H or C₁-C₁₅ alkyl; R₁ isCO₂R_(b2); in which R_(b2) is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, aryl, or heteroaryl; one of R₂ and R₃ is C₁-C₁₅alkyl substituted with halogen, OR_(c1), SR_(c1), CO₂R_(c1),OC(O)R_(c1), C(O)NR_(c1)R_(c2), SO₂R_(c1), O—SO₂—R_(c1), NR_(c1)R_(c2),O—SO₂—R_(c1), NR_(c1)R_(c1)R_(c2), N(R)_(c1))—C(O)R_(c1),N(R_(c1))—CO₂R_(c2), N(R_(c1))—SO₂R_(c2), orN(R_(c1))—C(O)—N(R_(c2)R_(c3)); the other of R₂ and R₃ is H, C₁-C₁₅alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl,OR_(c1), SR_(c1), or NR_(c1)R_(c2); in which each of R_(c1), R_(c2), andR_(c3), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; each of R₄ and R₅, independently,is H, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, or aryl; one of R₆ and R₇ is C₁-C₁₅ alkyl substituted with2-oxo-3-pyrrolidinyl; and the other of R₆ and R₇ is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; R₈ isH, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, aryl, OR_(d1), or SR_(d1); in which R_(d1) is H and C₁-C₁₅alkyl; and one of R₉ and R₁₀ is C(O)R_(e1); the other of R₉ and R₁₀ isH, halogen, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, aryl, C(O)R_(e1), CO₂ _(Re1), C(O)NR_(e1)R_(e2),C(O)—N(R_(e1))—OR_(e2), C(S)R_(e1), C(S)NR_(e1)R_(e2), CN, NO₂,S(O)R_(e1), SO₂R_(e1), S(O)NR_(e1)R_(e2), S(O)—N(R_(e1))—OR_(e2),SO₂NR_(e1)R_(e2), SO₃R_(e1), PO(OR_(e1)) (OR_(e2)), PO(R_(e1))(R_(e2)),PO(NR_(e1)R_(e2))(OR_(e3)), PO(NR_(e1)R_(e2))(NR_(e3)Re₄),C(O)—N(R_(e1))NR_(e2)R_(e3), or C(S)—N(R_(e1))—NR_(e2)R_(e3); in whicheach of R_(e1), R₂, R_(e3), and R₄, independently, is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; or anytwo of R_(e1), R_(e2), R_(e3), and R_(e4), together with the atom oratoms to which they are bonded, are C₃-C₂₀ heterocycloalkyl.
 7. Thecompound of claim 6, wherein X is N(R_(a1)); R₁ is CO₂R_(b2), in whichR_(b2) is alkyl substituted with aryl; one of R₂ and R₃ is C₁-C₁₅ alkylsubstituted with OR_(c1), SR_(c1), OC(O)R_(c1), CO₂R_(c1),C(O)NR_(c1)R₂, SO₂R_(c1), O—SO ₂-R_(c1), NR_(c1)R_(c2),N(R_(c1))—C(O)R_(c2), N(R_(c1))—CO₂R_(c2), N(R_(c1))—SO₂R_(c2), orN(R_(c1))—C(O)—N(R_(c2)R_(c3)), and the other of R₂ and R₃ is H; each ofR₄ and R₅, independently, is H or C₁-C₁₅ alkyl; one of R₆ and R₇ isC₁-C₁₅ alkyl substituted with 2-oxo-3-pyrrolidinyl, and the other of R₆and R₇ is H; and R₈ is H.
 8. The compound of claim 7, wherein one of R₆and R₇ is


9. The compound of claim 8, wherein one of R₄ and R₅ is H or C₁-C₁₅alkyl optionally substituted with aryl, C₃-C₂₀ cycloalkyl, OR_(f1),SR_(f1), NR_(f1)R _(f2), or C(O)NR_(f1)R_(f2); in which each of R_(f1)and R_(f2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl.
 10. The compound of claim 9,wherein the compound is


11. A pharmaceutical composition comprising a compound of claim 6 and apharmaceutically acceptable carrier.
 12. A compound of formula (I):

wherein X is N(R_(a1)); in which R_(a1) is H or C₁-C₁₅ alkyl; R₁ isCO₂R_(b2); in which R_(b2) is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, aryl, or heteroaryl; each of R₂ and R₃, independently,is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl,heteroaryl, aryl, OR_(c1), SR_(c1), or NR_(c1)R_(c2); in which each ofR_(c1) and R_(c2), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl,C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; one of R₄ and R₅ is C₁-C₁₅alkyl substituted with halogen, CO₂R_(d1), C(O)NR_(d1)R_(d2), SO₂R_(d1),SO₃R_(d1), or NR_(d1)R_(d2); the other of R₄ and R₅ is H, halogen,C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, oraryl; in which each of R_(d1) and R₂, independently, is H, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, or aryl; one ofR₆ and R₇ is C₁-C₁₅ alkyl substituted with 2-oxo-3-pyrrolidinyl; and theother of R₆ and R₇ is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; R₈ is H, halogen, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl, OR_(e1),or SR_(e1); in which R_(e1) is H and C₁-C₁₅ alkyl; and one of R₉ and R₁₀is C(O)R_(e1); the other of R₉ and R₁₀ is H, halogen, C₁-C₁₅ alkyl,C₃-C₂₀ cycloalkyl, C₃-C₂₀ heterocycloalkyl, heteroaryl, aryl,C(O)R_(f1), CO₂R_(f1), C(O)NR_(f1)R_(f2), C(O)—N(R_(f1))—OR_(f2),C(S)R_(f1), C(S)NR_(f1)R_(f2), CN, NO₂, S(O)R_(f1), SO₂R_(f1),S(O)NR_(f1)R_(f2), S(O)—N(R_(f1))—OR_(f2), SO₂NR_(f1)R_(f2), SO₃R_(f1),PO(OR_(f1))(OR_(f1)), PO(R_(f1))(R_(f2)), PO(NR_(f1)R_(f2))(OR_(f3)),PO(NR_(f1)R_(f2))(NR_(f3)R_(f4)), C(O)—N(R_(f1))—NR_(f2)R_(f3), orC(S)—N(R_(f1))—NR_(f2)R_(f3); in which each of R_(f1), R_(f2), R_(f3),and R_(f4), independently, is H, C₁-C₁₅ alkyl, C₃-C₂₀ cycloalkyl, C₃-C₂₀heterocycloalkyl, heteroaryl, or aryl; or any two of R_(f1), R_(f2),R_(f3), and R_(f4), together with the atom or atoms to which they arebonded, are C₃-C₂₀ heterocycloalkyl.
 13. The compound of claim 12,wherein X is N(R_(a1)); R₁ is CO₂R_(b2), in which R_(b2) is alkylsubstituted with aryl; each of R₂ and R₃, independently, is H or C₁-C₁₅alkyl optionally substituted with aryl; one of R₄ and R₅ is C₁-C₁₅ alkylsubstituted with C(O)NR_(d1)R_(d2), and the other of R₄ and R₅ is H; oneof R₆ and R₇ is C₁-C₁₅ alkyl substituted with 2-oxo-3-pyrrolidinyl, andthe other of R₆ and R₇ is H; and R₈ is H.
 14. The compound of claim 13,wherein one of R₆ and R₇ is


15. A pharmaceutical composition comprising a compound of claim 12 and apharmaceutically acceptable carrier.